Substituted cyclic hydroxamates as inhibitors of matrix metalloproteinases

ABSTRACT

The present invention provides compounds of the formula I: 
     
       
         
         
             
             
         
       
         
         
           
             its enantiomers, diastereomers, racemic mixtures thereof, prodrugs, crystalline forms, non-crystalline forms, amorphous forms thereof, solvates thereof, metabolites thereof, and pharmaceutically acceptable salts, wherein the ring A substituent groups are fully defined in the following disclosure. The compounds of formula I are inhibitors of metalloproteases such as matrix metalloproteases and sheddases, and are useful in treating diseases such as rheumatoid arthritis, psoriasis, neoplastic diseases, allergies and all those diseases wherein inhibition of MMPs is desirable.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.13/111,426, filed May 19, 2011, which is a continuation of U.S.application Ser. No. 12/070,310, filed Feb. 15, 2008, now U.S. Pat. No.7,973,041, which is a divisional of U.S. application Ser. No.10/965,215, filed Oct. 15, 2004, now U.S. Pat. No. 7,491,724, whichclaims the benefit of U.S. Provisional Appl. Ser. No. 60/586,646, filedJul. 12, 2004, U.S. Provisional Appl. Ser. No. 60/515,352, filed Oct.28, 2003, and U.S. Provisional Appl. Ser. No. 60/512,016, filed Oct. 17,2003, the entire disclosures of which are incorporated herein byreference.

FIELD OF THE INVENTION

The present invention relates to compounds which are useful in treatingdiseases, pathologic conditions and disorders associated with unwantedmetalloprotease activity. The instant invention is also directed tomatrix metalloprotease (MMPS) inhibitors and their use as medicinalagents. The present invention further relates to novel compounds andmedical methods of treatment of many diseases, and other disordersespecially those wherein inhibition of metalloprotease activity would beof benefit. More particularly, the present invention relates to cyclichydroxamate derivatives and their use as MMP's inhibitors especiallysheddase inhibitors and metalloprotease-disintegrins (ADAMs) inhibitors.

BACKGROUND OF THE INVENTION

Most tissues exist in a highly regulated dynamic equilibrium wherein newtissue is formed and existing tissue is degraded and eliminated. Thedegradation of the extracellular matrix (ECM), including connectivetissue and basement membranes, is effected by the metalloproteinaseswhich are released from connective tissue and invading inflammatorycells. Excessive unregulated activity of these enzymes can result inundesirable tissue destruction and their activity is regulated at thetranscription level, by controlled activation of the latent proenzymeand, after translation, by intracellular specific inhibitory factorssuch as TIMP (“Tissue Inhibitors of MetalloProteinase”) or by moregeneral proteinase inhibitors such as α2-macroglobulins.

Several structurally related metalloproteases (MPs) are known to play animportant role in the breakdown of structural proteins. Thesemetalloproteases typically act on the intercellular matrix, and thus areinvolved in tissue breakdown and remodeling. Such proteins have beenreferred to as metalloproteases or MPs. There are several differentfamilies of MPs, classified by sequence homology. Several families ofknown MPs, as well as examples thereof, are disclosed in the art.

These MPs include Matrix-Metallo Proteases [MMPs], zincmetalloproteases, many of the membrane-bound metalloproteases, TNFconverting enzymes, angiotensin-converting enzymes (ACEs), disintegrins,including ADAMs (See Wolfsberg et al, 131 J. Cell Bio. 275-78 Oct. 25,1995), and the enkephalinases. Examples of MPs include human skinfibroblast collagenase, human skin fibroblast gelatinase, human sputumcollagenase, aggrecanase and gelatinase, and human stromelysin.Collagenase, stromelysin, aggrecanase and related enzymes are thought tobe important in mediating the symptomatology of a number of diseases.

Zinc proteases are subdivided according to the primary structure oftheir catalytic sites and include gluzincin, metzincin, inuzincin,carboxypeptidase, and DD carboxypeptidase subgroups (Hooper N M, 1994,FEBS Lett, 354:1-6). The metzincin subgroup is further divided intoserralysins, astacins, matrixins, and adamalysins (Stocker W and Bode W,1995, Curr Opin Struct Biol, 5:383-390).

The matrixins include the matrix metalloproteases, or MMPs. MMPsconstitute a family of structurally similar zinc-containingmetalloproteases, which are involved in the remodeling and degradationof extracellular matrix proteins, both as part of normal physiologicalprocesses and in pathological conditions. For a review see Bode, W etal., 1996, Adv Exp Med Biol, 389:1-11. Connective tissue, extracellularmatrix constituents and basement membranes are the biological materialsthat provide rigidity, differentiation, attachment sites and, in somecases, elasticity to biological systems. Connective tissue componentsinclude, for example, collagen, elastin, proteoglycans, fibronectin andlaminin that form the scaffold for all human tissues. Under normalconditions, connective tissue turnover and/or repair processes arecontrolled and in equilibrium. The loss of this balance, for whateverreason, leads to a number of disease states Inhibition of the enzymesresponsible for loss of equilibrium provides a control mechanism forthis tissue decomposition and, therefore, a treatment for thesediseases. The uncontrolled breakdown of connective tissue bymetalloproteases is a feature of many pathological conditions.

Besides a role in the regulation of extracellular matrix, there is alsoevidence to suggest that MMPs mediate the migration of inflammatorycells into tissues (Moscatelli D and Rifkin D B, 1988, Biochim BiophysActa, 948: 67-85). Several reports have demonstrated that various MMPscan activate a variety of important non-matrix proteins, includingcytokines, chemokines, integrins, and antimicrobial peptides (see ParksW C, 2002, J Clin Invest, 110:613-4). Many of the human MMPs areover-expressed in human tumors and are associated with peritumor tissuedegradation and metastasis formation. Another important function ofcertain MMPs is to activate various enzymes, including other MMPs, bycleaving the pro-domains from their protease domains. Thus some MMPs actto regulate the activities of other MMPs, so that over-production of oneMMP may lead to excessive proteolysis of extracellular matrix byanother. It has also been reported that MMPs can cleave and therebyinactivate the endogenous inhibitors of other proteinases such aselastase (Winyard P G et al., 1991, FEBS Letts, 279: 91-94) Inhibitorsof MMPs could thus influence the activity of other destructiveproteinases by modifying the level of their endogenous inhibitors. Inaddition, increasing or maintaining the levels of an endogenous oradministered serine protease inhibitor supports the treatment andprevention of diseases such as emphysema, pulmonary diseases,inflammatory diseases and diseases of aging (such as loss of skin ororgan stretch and resiliency.) Thus, MMPs should not be viewed solely asproteinases of ECM catabolism, but rather as extracellular processingenzymes involved in regulating cell-cell and cell-ECM signaling events.

The adamalysins include the reprolysins, snake venom metalloproteasesand the ADAMs. The ADAMs (a disintegrin and metalloprotease domain) arean important family of metalloproteases. They are a family of type Itransmembrane glycoproteins that are important in diverse biologicprocesses, such as cell adhesion and the proteolytic shedding of cellsurface receptors. ADAM family members have been identified frommammalian and non-mammalian sources, including Xenopus, Drosophila, andCaenorhabditis elegans. Members of the family have a modular design,characterized by the presence of metalloprotease and integrinreceptor-binding activities, and a cytoplasmic domain that in manyfamily members specifies binding sites for various signal-transducingproteins. The ADAMs family has been implicated in the control ofmembrane fusion, cytokine, growth factor and growth factor receptorshedding, and cell migration, as well as processes such as muscledevelopment, fertilization, neurogenesis, and cell fate determination.Loss of regulation can lead to disease and pathology. Pathologies suchas infertility, inflammation and cancer have been shown to involve ADAMsfamily members. For a review, see Wolfsberg T G and White J M, 1998,ADAM metalloproteinases. In Handbook of Proteolytic Enzymes (Barrett AJ, Rawlings N D and Woessner J F eds), p. 1310-1313, Academic Press,London as well as Seals D F and Courtneidge S A, 2003, Genes andDevelopment, 17:7-30.

Some specific examples of important ADAM metalloproteases include theTNFα-converting enzyme, TACE or ADAM17, that is currently an importanttarget for anti-inflammatory drugs (Moss M L et al., 2001, Drug DiscovToday, 6:417-426 and Black R A, 2002, Int J Biochem Cell Biol, 34:1-5).Other members of the family are also likely to be good therapeutictargets. ADAM8 has been reported to be expressed almost exclusively incells of the immune system, particularly B-cells, monocytes, eosinophilsand granulocytes. ADAM8 therefore represents a therapeutic target forhuman immunologically-based diseases. ADAM15 is found in human aorticsmooth muscle and cultured umbilical vein endothelial cells. WhileADAM15 is not expressed in normal blood vessels, it has been detected indeveloping atherosclerotic lesions (Herren B et al., 1997, FASEB J,11:173-180), and has also been shown to be up-regulated inosteoarthritic versus normal human cartilage (Bohm B B et al., 1999,Arthritis Rheum, 42:1946-1950). Thus ADAM15 may play a role inatherosclerosis and cartilage degenerative diseases. In addition, ADAM15knockout mice have reduced neovascularization and smaller tumorscompared to wildtype controls, suggesting that ADAM15 may also beimportant in cancer (Horiuchi, K et al., 2003, Mol Cell Biol,23:5614-5624.) The lymphocyte-specific expression of the ADAM28 suggeststhat it may have an important immunological function.

Excessive production of IgE is believed to be a major mediator ofallergic responses. CD23, the low affinity receptor for IgE, is subjectto ADAM-type metalloprotease-dependent proteolytic release of solubleextracellular fragments, which have been shown to cause upregulation ofIgE production and induction of inflammatory cytokines (see Novak N etal, 2001, Curr Opin Immunol, 13:721-726 and Mayer R J et al., 2002,Inflamm Res, 51:85-90). Increased levels of soluble CD23 have beenobserved in allergic asthma, in chronic B-lymphocytic leukemia and inrheumatoid arthritis. Inhibition of the enzyme(s) responsible for CD23processing may offer a therapeutic approach for the treatment of variousimmune-based diseases. ADAM metalloproteases also appear to beresponsible for the release or shedding of soluble receptors (forexample, CD30 and receptors for TNF), adhesion molecules (for example,L-selectin, ICAM-1, fibronectin), growth factors and cytokines (forexample Fas ligand, TGF-α, EGF, HB-EGF, SCF IL-6, IL-1, TSH and M-CSF),and growth factor receptors (for example EGFR family members, such asHer-2 and Her-4, which have been implicated in the pathogenesis ofdifferent types of cancer) (Yarden Y and Sliwkowski M X, 2001, NatureReviews 2:127-137). For example, Her-2 is over-expressed in 25-30% ofhuman breast cancers and is associated with an increased risk of relapseand death (Slamon D J et al, 1987, Science, 235:177-182). ADAM17 hasrecently been shown to be critical for the regulated shedding of Her-4(Rio C et al, 2000, J Biol Chem, 275:10379-10387). The proteaseresponsible for Her-2 cleavage, known as Her-2 sheddase, is an unknownMMP that may also be a member of the ADAM family (Codony-Servat J et al,1999, Cancer Res 59:1196-1201). Modulation of this activity mighttherefore have an important role in the modulation of human disease. Fora review of the sheddase activity of ADAMs see Moss M L and Lambert M H,2002, Essays Biochem, 38:141-153.

ADAM-TS (also shown as “ADAMTS”) proteases have been identified asmembers of the ADAM family. These proteins are novel in that theycontain unique thrombospondin (TS) type I motifs in addition to some ofthe structurally conserved domains of other ADAM family members. TheADAM-TSs are also distinguished from the ADAMs by their lack ofcysteine-rich, EGF-like, transmembrane, and cytoplasmic domains. ADAM-TSproteins have also been shown to be associated with a number ofpathological or human disease states. For example, ADAMTS-1 is atumor-selective gene expressed in colon tumor cells and is also aninflammation-associated protein. A human ortholog of ADAMTS-1, known asMETH-1, and the related protein METH-2 have been recently shown to haveantiangiogenic activity, and these or other ADAM-TS family members mayplay important roles in regulating vascular development. ADAMTS-2 hasbeen implicated in the normal development of the skin. This enzyme waslong known as procollagen N-proteinase, a proteinase thatproteolytically removes amino peptides in the processing of type I andtype II procollagens to collagens, and it was shown to be deficient inthe skin of individuals with the inherited connective tissue disordertype VIIC Ehlers-Danros syndrome. ADAMTS-4 and ADAMTS-11 are known asaggrecanase-1 and -2 because of their ability to cleave specific sitesin aggrecan, a proteoglycan that maintains the mechanical properties ofcartilage. Progressive degradation and depletion of aggrecan has beenimplicated in degenerative joint diseases such as osteoarthritis andinflammatory joint diseases such as rheumatoid arthritis. For a reviewof the ADAM-TS metalloproteases see Tang B L, 2001, Int J Biochem CellBiol, 33:33-44 and Kaushal G P and S V Shah, 2000, J Clin Invest105:1335-1337.

The metalloproteases are one of the older classes of proteinases and arefound in bacteria, fungi as well as in higher organisms. Many enzymescontain the sequence HEXXH, which provides two histidine ligands for thezinc, whereas the third ligand is either a glutamic acid (thermolysin,neprilysin, alanyl aminopeptidase) or a histidine (astacin). Otherfamilies exhibit a distinct mode of binding of the Zn atom.Metalloproteases have therefore been isolated from a number ofprokaryotic and eukaryotic sources. Acidic metalloproteases have beenisolated from broad-banded copperhead and rattlesnake venoms. Neutralmetalloproteases, specifically those having optimal activity at neutralpH have, for example, been isolated from Aspergillus sojae. Alkalinemetalloproteases, for example, have been isolated from Pseudomonasaeruginosa and the insect pathogen Xenorhabdus luminescens. Inhibitionof microbial metalloproteases may lead to growth inhibition andrepresent an antibiotic strategy. Inhibition of metalloproteasesassociated with snake venom or insect toxicity may also lead to newtherapeutic strategies.

Potential therapeutic indications of MP inhibitors have been discussedin the literature. See for example, U.S. Pat. No. 6,500,847 (BayerCorporation), U.S. Pat. No. 6,268,379 (DuPont Pharmaceuticals Company),U.S. Pat. No. 5,968,795 (Bayer Corporation), U.S. Pat. No. 5,892,112(Glycomed Incorporated and The University of Florida), and U.S. Pat. No.5,872,152 (British Biotech Pharmaceuticals Limited).

Matrix metalloprotease inhibitors are useful in treating diseasescaused, at least in part, by breakdown of structural proteins. Althougha variety of MMP inhibitors have been prepared in the relevant field,there is a continuing need for potent matrix metalloprotease inhibitorsuseful in treating diseases caused, at least in part, by breakdown ofstructural proteins. Applicants have found that, surprisingly, thecompounds of the present invention are potent metalloproteaseinhibitors.

OBJECTS OF THE INVENTION

With the foregoing in mind, it is an object of the present invention toprovide a novel class of substituted carbocyclic or substitutedheterocyclic compounds of the formulae I and IA, possessing therapeuticutility as metalloprotease inhibitors.

It is another object of the invention to provide a smaller class(relative to formula I) of novel substituted carbocyclic or substitutedheterocyclic compounds of the formulae II and IIA, possessingtherapeutic utility as metalloprotease inhibitors.

It is a further object of the invention to identify and claim a smallerclass (relative to formuale I and II) of novel, substituted, cyclichydroxamate derivatives of the formulae III, IIIA, IV, and IVApossessing therapeutic utility as metalloprotease inhibitors.

It is an additional object of the invention to identify and claim asmaller class (relative to formuale I and II) of novel, substituted,cyclic hydroxamate derivatives of the formula V, VA, VI, and VIApossessing therapeutic utility as metalloprotease inhibitors.

It is a further object of the invention to provide compounds of theformulae I, IA, II, IIA, III, IIIA, IV, IVA, V VA, VI, and VIApossessing one or more therapeutic utilities as a matrix metalloprotease(MMP) inhibitor, a sheddase inhibitor, and an ADAM inhibitor.

Another object of the invention to provide pharmaceutically usefulcompositions comprising such metalloprotease inhibitors, or morespecifically MMP inhibitor, sheddase inhibitor, and/or ADAM inhibitor,of the formulae I, IA, II, IIA, III, IIIA, IV, IVA, V VA, VI, and VIA intherapeutically effective quantities in conjunction with one or morepharmaceutically acceptable carriers and/or excipients.

Yet another object of the invention is to provide a method of treatmentfor metalloprotease-related maladies or conditions and disease statesthat are characterized by unwanted metalloprotease activity.

It is another object to use the compounds of the invention inmethodologies for treating allergic conditions.

It is an object of the invention to provide Her-2 sheddase inhibitingcompounds and also a further embodiment of utilizing compositionscomprising such Her-2 sheddase inhibitors to treat neoplastic diseases.

It is a further object of the invention to provide compounds that areinhibitors of ADAM 10, ADAM15, ADAM28, ADAM33 embodied as anti-canceragents.

It is a further object of the invention to provide compounds that areinhibitors of ADAM17/TACE (a.k.a. TNF alpha convertase) embodied asanti-inflammatory agents, and further embodied in methodologies fortreating inflammatory disease states.

Further still, an object of the invention is to provide compounds thatare inhibitors of matrix metalloprotease 12 (a.k.a. MMP 12) embodied asanti-inflammatory agents, and further embodied in methodologies fortreating inflammatory disease states.

Additionally, the invention provides novel selective, small moleculeinhibitors of matrix metalloproteinases which can be used to modulatethe progression of the underlying diseases and to treat diseasesassociated with excessive MMP-induced tissue damage.

Other objects and embodiments of the present invention will be discussedbelow. However, there are additional embodiments of the invention, notspecifically enumerated or described in the following specification, butwhich nevertheless fall within the spirit and scope of the subjectmatter of the present disclosure and of the appended claims. Theseadditional embodiments will be readily appreciated by one skilled in theart without resort to undue experimentation.

SUMMARY OF THE INVENTION

The present invention provides, in its broadest embodiment, compoundshaving the formula IA:

its enantiomers, diastereomers, enantiomerically enriched mixtures,racemic mixtures thereof, prodrugs, crystalline forms, non-crystallineforms, amorphous forms thereof, solvates thereof, metabolites thereof,and pharmaceutically acceptable salts, wherein:

ring A is a 3-13 membered carbocycle or heterocycle comprising carbonatoms, 0-3 carbonyl groups, 0-4 double bonds, and from 0-4 ringheteroatoms selected from the group consisting of O, N, NR, andS(O)_(p), provided that ring A contains other than a S—S, O—O, or S—Obond;

n′ is an integer from 1-3;

Z is selected from the group consisting of —COR⁵, —CO₂H, —CH₂CO₂H,—CO₂R⁶, —CONHOH, —CONHOR⁵, —CON(R⁶)OH, —CONHOR⁶, —NHR^(a), —N(OH)C(O)R⁵,—N(OH)CHO, —SH, —CH₂SH, —S(O)(═NH)R^(a), —SN₂H₂R^(a), —PO(OR^(g))₂,—PO(OH)NHR^(a),

R^(g) is independently selected from the group consisting of H,CH₂OCOR^(a), P is D-E-G-Q-L-T-X-Y, wherein

D is absent or is selected from the group consisting of O, NR^(a1),C(O), C(O)O, OC(O), C(O)NR^(a1), NR^(a1)C(O), OC(O)O, OC(O)NR^(a1),NR^(a1)C(O)O, NR^(a1)C(O)NR^(a1), S(O)_(p), S(O)_(p)NR^(a1),NR^(a1)S(O)_(p), and NR^(a1)SO₂NR^(a1);

E is absent or is selected from the group consisting of C₁₋₁₀alkylene,C₂₋₁₀ alkenylene, and

C₂₋₁₀ alkynylene;

G is absent or is selected from the group consisting of O, NR^(a1),S(O)_(p), and C(O);

Q is absent or is selected from the group consisting of a C₃₋₁₃carbocycle substituted with 0-5 R^(b), and a 5-14 membered heterocyclecomprising carbon atoms and 1-4 heteroatoms selected from the groupconsisting of N, O, and S(O)_(p), and said heterocycle being substitutedwith 0-5 R^(b);

L is absent or is selected from the group consisting of O, NR^(a1),C(O), C(O)O, OC(O), C(O)NR^(a1), NR^(a1)C(O), OC(O)O, OC(O)NR^(a1),NR^(a1)C(O)O, NR^(a1)C(O)NR^(a1), S(O)_(p), S(O)_(p)NR^(a1),NR^(a1)S(O)_(p), and NR^(a1)SO₂NR^(a1);

T is absent or is selected from the group consisting of C₁₋₁₀ alkylene,C₂₋₁₀ alkenylene, and C₂₋₁₀ alkynylene;

X is absent or is selected from the group consisting of O, NR^(a1),S(O)_(p), and C(O);

Y is selected from the group consisting of H, a C₃₋₁₃ carbocyclesubstituted with 0-5 R^(c) and a 5-14 membered heterocycle comprisingcarbon atoms and 1-4 heteroatoms selected from the group consisting ofN, O, and S(O)_(p), and said heterocycle being substituted with 0-5R^(c);

provided that D, E, G, Q, L, T, X and Y do not combine to form a N—N,N—O, O—N, O—O, S(O)_(p)—O, O—S(O)_(p) or S(O)_(p)—S(O)_(p) group;

R, at each occurrence, is independently selected from (C₁₋₁₀ alkylenesubstituted with

1-3R^(b1))-M, (C₂₋₁₀ alkenylene substituted with 1-3 R^(b1))-M, (C₂₋₁₀alkynylene substituted with 1-3 R^(b1))-M, OH, Cl, F, Br, I, —CN, NO₂,CF₃, CF₂CF₃, CH₂F, CHF₂, CF₂CH₃, C(CH₃)₂F, OCF₃, OCHF₂, OCF₂CF₃,O(CR^(d)R^(d1))_(r)-M, NR^(a)(CR^(d)R^(d1))_(r)-M,OC(O)(CR^(d)R^(d1))_(r)-M, NR^(a)C(O)(CR^(d)R^(d1))_(r)-M,OC(O)O(CR^(d)R^(d1))_(r)-M, OC(O)NR^(a)(CR^(d)R^(d1))_(r)-M,NR^(a)C(O)O(CR^(d)R^(d1))_(r)-M, NR^(a)C(O)NR^(a1)(CR^(d)R^(d1))_(r)-M,S(O)_(p)(CR^(d)R^(d1))_(r)-M, S(O)₂NR^(a)(CR^(d)R^(d1))_(r)-M,NR^(a)S(O)₂(CR^(d)R^(d1))_(r)-M, andNR^(a)S(O)₂NR^(a1)(CR^(d)R^(d1))_(r)-M, (CR^(d)R^(d1))_(r)P(O)(OR^(a))₂,(CR^(d)R^(d1))_(r)P(O)(OR^(a))(NR^(d)R^(d1)),(CR^(d)R^(d1))_(r)P(O)(NR^(a)R^(a1))₂, (CR^(d)R^(d1))_(r)OP(O)(OR^(a))₂,(CR^(d)R^(d1))_(r)OP(O)(OR^(a))(NR^(a)R^(a1)),(CR^(d)R^(d1))_(r)OP(O)(NR^(a)R^(a1))₂,(CR^(d)R^(d1))_(r)NR^(a)P(O)(OR^(a))₂,(CR^(d)R^(d1))_(r)NR^(a)P(O)(OR^(a))(NR^(a)R^(a1)),(CR^(d)R^(d1))_(r)NR^(a)P(O)(NR^(a)R^(a1))₂; C(═NR^(a))NR^(a1)R^(a2);C(═CR^(d)R^(d1))NR^(a1)R^(a2); a C₃₋₁₃ carbocycle substituted with 0-5R^(d), and a 5-14 membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from the group consisting of N, O, S(O)_(p) andsaid heterocycle being substituted with 0-5 R^(d); alternatively, two R,together with a carbon atom on A, form the group C_(A)═CR^(d)R^(d1),where the atom C_(A) is said atom on A;

M is selected from the group consisting of H, C₂₋₁₀ alkenylenesubstituted with 0-3 R^(b1),

C₂₋₁₀ alkynylene substituted with 0-3 R^(b1), OR^(a), Cl, F, Br, I, —CN,NO₂, NR^(a)R^(a1), C(O)R^(a), C(O)OR^(a), C(O)NR^(a)R^(a1),R^(a)NC(O)NR^(a)R^(a1), OC(O)NR^(a)R^(a1), NR^(a)C(O)OR^(a),NR^(a)C(O)R^(a), S(O)₂NR^(a)R^(a1), NR^(a)S(O)₂R^(a2),NR^(a)S(O)₂NR^(a)R^(a1), OS(O)₂NR^(a)R^(a1), S(O)_(p)R^(a2), CF₃,CF₂CF₃, CH₂F, CHF₂, CF₂CH₃, C(CH₃)₂F, OCF₃, OCF₂CF₃, OCHF₂, a C₃₋₁₃carbocycle substituted with 0-5 R^(d), and a 5-14 membered heterocyclecomprising carbon atoms and 1-4 heteroatoms selected from the groupconsisting of N, O, S(O)_(p) and said heterocycle being substituted with0-5 R^(d);

alternatively, R, at each occurrence, is independently selected from aC₁₋₁₀ alkylene-M¹,

C₂₋₁₀ alkenylene-M¹, C₂₋₁₀ alkynylene-M¹,(CR^(d)R^(d1))_(r)O(CR^(d)R^(d1))_(r)-M¹,

(CR^(d)R^(d1))_(r)NR^(a)(CR^(d)R^(d1))_(r)-M¹, (CR^(d)R^(d1))_(r)C(O)(CR^(d)R^(d1))_(r)-M¹,

(CR^(d)R^(d1))_(r)C(O)O(CR^(d)R^(d1))_(r)-M¹,(CR^(d)R^(d1))_(r)OC(O)(CR^(d)R^(d1))_(r)-M¹,

(CR^(d)R^(d1))_(r)C(O)NR^(a)(CR^(d)R^(d1))_(r)-M¹,(CR^(d)R^(d1))_(r)NR^(a)C(O)(CR^(d)R^(d1))_(r)-M¹,

(CR^(d)R^(d1))_(r)OC(O)O(CR^(d)R^(d1))_(r)M¹,(CR^(d)R^(d1))_(r)OC(O)NR^(a)(CR^(a)R^(a1))_(r)-M¹,

(CR^(d)R^(d1))_(r)NR^(a)C(O)O(CR^(d)R^(d1))_(r)-M¹,(CR^(d)R^(d1))_(r)NR^(a)C(O)NR^(a1)(CR^(d)R^(d1))_(r)-M¹,(CR^(d)R^(d1))_(r)S(O)_(p)(CR^(d)R^(d1))_(r)-M¹,(CR^(d)R^(d1))_(r)S(O)₂NR^(a)(CR^(d)R^(d1))_(r)-M¹,(CR^(d)R^(d1))_(r)NR^(a)S(O)₂(CR^(d)R^(d1))_(r)-M¹, and(CR^(d)R^(d1))_(r)NR^(a)S(O)₂NR^(a1)(CR^(d)R^(d1))_(r)M¹;

M¹ is selected from the group consisting of OR^(a), Cl, F, Br, I, —CN,NO₂, NR^(a)R^(a1), C(O)R^(a), C(O)OR^(a), C(O)NR^(a)R^(a1),R^(a)NC(O)NR^(a)R^(a1), OC(O)NR^(a)R^(a1), R^(a)NC(O)OR^(a),S(O)₂NR^(a)R^(a1), NR^(a)S(O)₂R^(a2), NR^(a)S(O)₂NR^(a)R^(a1),OS(O)₂NR^(a)R^(a1), S(O)_(p)R^(a2), CF₃, CF₂CF₃, CH₂F, CHF₂, CF₂CH₃,C(CH₃)₂F, OCF₃, OCF₂CF₃ and a 5-14 membered non-aromatic heterocyclecomprising carbon atoms and 1-4 heteroatoms selected from the groupconsisting of N, O, S(O)_(p) and said heterocycle being substituted with0-5 R^(d); a C₃-C₁₃ carbocycle, C₄-C₁₄ heterocycle and wherein saidC₃-C₁₃ carbocycle and C₄-C₁₄ heterocycle are substituted with 1-3 R^(h),and CF₃, CF₂CF₃, CH₂F, CHF₂, CF₂CH₃, C(CH₃)₂F, OCF₃, OCHF₂, OCF₂CF₃ andOCH₂CF₃;

alternatively, when two R groups are attached to adjacent ring A atoms,together with the atoms to which they are attached they may form a 3-8membered saturated, partially saturated or unsaturated ring comprised ofcarbon atoms and 0-3 heteroatoms selected from the group consisting ofN, NR^(a), O, and S(O)_(p), wherein said ring may be benzene-fusedand/or substituted with R^(d);

alternatively, when two R groups are attached to the same ring A carbon,together with the carbon to which they are attached they may form a 3-8membered saturated, partially saturated or unsaturated spiro-ringcomprised of carbon atoms and 0-3 heteroatoms selected from the groupconsisting of N, NR^(a), O, and S(O)_(p), wherein said spiro-ring may bebenzene-fused and/or substituted with R^(d);

provided that either two or more R or M, M¹ and the atom to which theyare attached do not combine to form a N—N, N—O, O—N, O—O, N-halogen,O-halogen, S-halogen, S(O)_(p)—O, O—S(O)_(p), S(O)_(p)—S(O)_(p) group,or C(O)F, C(O)Cl, C(O)Br, or C(O)I reactive group;

R^(a), R^(a1), and R^(a2) at each occurrence are independently selectedfrom the group consisting of H, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈alkynyl, wherein said alkyl, alkenyl and alkynyl groups are optionallysubstituted with O (primary, secondary, or tertiary)C₁-C₈, OH, Cl, F,Br, I, ═O, —CN, NO₂, alkylamino, dialkylamino, alkarylamino, arylamino,alkylcarbonyl, aralkylcarbonyl, arylcarbonyl, carboxyl,alkylcarboxylate, alkylamido, dialkylamido, alkylureidoalkyl,alkylureidodialkyl, carbamoylalkyl, carbamoyldialkyl, alkylcarbamoyl,sulfonamidoalkyl, sulfonamidodialkyl, N-alkylsulfonamidoalkyl,N-alkylsulfonamidoalkyl, N-alkylsufonamidodialkyl, alkylamidosulfonate,dialkylamidosulfonate, alkylsulfinyl, alkylsulfonyl, CF₃, CF₂CF₃, CH₂F,CHF₂, CF₂CH₃, C(CH₃)₂F, OCF₃, OCF₂CF₃ and OCH₂CF₃; C₃-C₁₀ carbocycle,heterocycles, C₃-C₁₀ carbocyclylalkyl, heterocyclylalkyl and whereinsaid C₃-C₁₀ carbocycle, heterocycles, C₃-C₁₀ carbocyclylalkyl, andheterocyclylalkyl may be optionally substituted with one or moresubstituents selected from the group consisting of C₁-C₈ alkyl, O(primary, secondary, or tertiary) C₁-C₈, OH, C₁, F, Br, I, ═O, —CN, NO₂,alkylamino, dialkylamino, alkarylamino, arylamino, alkylcarbonyl,aralkylcarbonyl, arylcarbonyl, carboxyl, alkylcarboxylate, alkylamido,dialkylamido, alkylureidoalkyl, alkylureidodialkyl, carbamoylalkyl,carbamoyldialkyl, alkylcarbamoyl, sulfonamidoalkyl, sulfonamidodialkyl,N-alkylsulfonamidoalkyl, N-alkylsulfonamido-alkyl,N-alkylsufonamidodialkyl, alkylamidosulfonate, dialkylamidosulfonate,alkylsulfinyl, alkylsulfonyl, CF₃, CF₂CF₃, CH₂F, CHF₂, CF₂CH₃, C(CH₃)₂F,OCF₃, OCF₂CF₃ and OCH₂CF₃; alternatively, R^(a) and R^(a1) takentogether with the nitrogen to which they are attached form a 4 to 8membered ring containing from 0-1 additional heteroatoms selected fromthe group consisting of N, O, and S, wherein said ring may besubstituted with R^(d);

R^(b) at each occurrence is independently selected from the groupconsisting of C₁₋₆ alkyl optionally substituted with R^(c1), O (primary,secondary, or tertiary) C₁-C₈, OH, Cl, F, Br, I, ═O, —CN, NO₂,NR^(a)R^(a1), C(O)R^(a), C(O)OR^(a), C(O)NR^(a)R^(a1),R^(a)NC(O)NR^(a)R^(a), OC(O)NR^(a)R^(a1), R^(a)NC(O)OR^(a1),S(O)₂NR^(a)R^(a1), NR^(a)S(O)₂R^(a2), NR^(a)S(O)₂NR^(a)R^(a1),OS(O)₂NR^(a)R^(a1), S(O)_(p)R^(a2), CF₃, CF₂CF₃, CH₂F, CHF₂, CF₂CH₃,C(CH₃)₂F, OCF₃, OCHF₂, OCF₂CF₃ and OCH₂CF₃; C₃₋₁₀ carbocyclic residue,and a 5-14 membered heterocyclic system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S, C₃-C₁₀carbocyclyl(C₁₋₈)alkyl, and 5-14 heterocyclyl-(C₁₋₈)alkyl and said C₃₋₁₀carbocyclic residue, heterocyclic system,

C₃-C₁₀ carbocyclyl(C₁₋₈)alkyl, and 5-14 heterocyclyl(C₁₋₈)alkyl areoptionally substituted with R^(c1);

R^(b1) at each occurrence is independently selected from the groupconsisting of OR^(a), F, ═O, —CN, NO₂, NR^(a)R^(a1) and S(O)_(p)R^(a);

R^(c) at each occurrence is independently selected from the groupconsisting of C₁₋₆ alkyl optionally substituted with R^(c1), OR^(a), Cl,F, Br, I, ═O, —CN, NO₂, NR^(a)R^(a1), C(O)R^(a), C(O)OR^(a),C(O)NR^(a)R^(a1), R^(a)NC(O)NR^(a)R^(a), OC(O)NR^(a)R^(a1),R^(a)NC(O)OR^(a1), S(O)₂NR^(a)R^(a1),

NR^(a)S(O)₂R^(a1), NR^(a)S(O)₂NR^(a)R^(a1), OS(O)₂NR^(a)R^(a1),S(O)_(p)R^(a1), CF₃, CF₂CF₃, CH₂F, CHF₂, CF₂CH₃, C(CH₃)₂F, OCF₃, OCHF₂,OCF₂CF₃ and OCH₂CF₃; a C₃₋₁₀ carbocyclic residue, and a 5-14 memberedheterocyclic system containing from 1-4 heteroatoms selected from thegroup consisting of N, O, and S, C₃-C₁₀ carbocyclyl(C₁₋₈)alkyl, and 5-14heterocyclyl(C₁₋₈)alkyl; said C₃₋₁₀ carbocyclic residue, heterocyclicsystem C₃-C₁₀ carbocyclyl(C₁₋₈)alkyl, and 5-14 heterocyclyl(C₁₋₈)alkylare optionally substituted with R^(c1).

R^(c1) at each occurrence is independently selected from the groupconsisting of C₁₋₆ alkyl, OR^(a), Cl, F, Br, I, ═O, —CN, NO₂,NR^(a)R^(a1), C(O)R^(a), C(O)OR^(a), C(O)NR^(a)R^(a1),OC(O)NR^(a)R^(a1), R^(a)NC(O)OR^(a), S(O)₂NR^(a)R^(a1),NR^(a)S(O)₂R^(a2), NR^(a)S(O)₂NR^(a)R^(a1), S(O)_(p)R^(a2), CF₃, andCF₂CF₃, CH₂F, and CHF₂;

R^(d) at each occurrence is independently selected from the groupconsisting of H, C₁₋₆ alkyl optionally substituted with R^(c1), OR^(a),Cl, F, Br, I, ═O, —CN, NO₂, NR^(a)R^(a1), C(O)R^(a), C(O)OR^(a),C(O)NR^(a)R^(a1), R^(a)NC(O)NR^(a)R^(a), OC(O)NR^(a)R^(a1),R^(a)NC(O)OR^(a1), S(O)₂NR^(a)R^(a1),

NR^(a)S(O)₂R^(a1), NR^(a)S(O)₂NR^(a)R^(a1), OS(O)₂NR^(a)R^(a1),S(O)_(p)R^(a1), CF₃, CF₂CF₃, CH₂F, CHF₂, CF₂CH₃, C(CH₃)₂F, OCF₃, OCHF₂,OCF₂CF₃ and OCH₂CF₃; C₃₋₁₀ carbocyclic residue, and a 5-14 memberedheterocyclic system containing from 1-4 heteroatoms selected from thegroup consisting of N, O, and S, C₃-C₁₀ carbocyclyl(C₁₋₈)alkyl, and 5-14heterocyclyl(C₁₋₈)alkyl; said C₃₋₁₀ carbocyclic residue, heterocyclicsystem C₃-C₁₀ carbocyclyl(C₁₋₈)alkyl, and 5-14 heterocyclyl(C₁₋₈)alkyloptionally substituted with R^(c1).

R^(d1) at each occurrence is independently selected from the groupconsisting of H, C₁₋₆ alkyl optionally substituted with R^(c1), OR^(a),Cl, F, Br, I, ═O, —CN, NO₂, NR^(a)R^(a1), C(O)R^(a), C(O)OR^(a),C(O)NR^(a)R^(a1), R^(a)NC(O)NR^(a)R^(a), OC(O)NR^(a)R^(a1),R^(a)NC(O)OR^(a1), S(O)₂NR^(a)R^(a1), NR^(a)S(O)₂R^(a1),NR^(a)S(O)₂NR^(a)R^(a1), OS(O)₂NR^(a)R^(a1), S(O)_(p)R^(a1), CF₃,CF₂CF₃, CH₂F, CHF₂, CF₂CH₃, C(CH₃)₂F, OCF₃, OCHF₂, OCF₂CF₃ and OCH₂CF₃;C₃₋₁₀ carbocyclic residue, and a 5-14 membered heterocyclic systemcontaining from 1-4 heteroatoms selected from the group consisting of N,O, and S, C₃-C₁₀ carbocyclyl(C₁₋₈)alkyl, and 5-14heterocyclyl(C₁₋₈)alkyl; said C₃₋₁₀ carbocyclic residue, heterocyclicsystem C₃-C₁₀ carbocyclyl(C₁₋₈)alkyl, and 5-14 heterocyclyl(C₁₋₈)alkyloptionally substituted with R^(c1).

alternatively, R^(d) and R^(d1) taken together with the atom to whichthey are attached form a 4 to 8 membered ring containing from 0-1heteroatoms selected from the group consisting of N, O, and S, whereinsaid ring may be substituted with R^(d);

R^(h) at each occurrence is independently selected from the groupconsisting of OR, NR^(j)R^(a), COR^(j), C(O)OR^(j), C(O)NR^(j)R^(a),NR^(a)C(O)NR^(j)R^(a1), OC(O)NR^(j)R^(a), S(O)_(p)NR^(j)R^(a1),NR^(a)S(O)pR^(j), NR^(a)S(O)pNR^(j)R^(a), C₁₋₆ alkyl substituted withR^(c).

R^(j) at each occurrence is independently selected from the groupconsisting of CF₃, CH₂F, CHF₂, CF₂CF₃, C1-C8 alkyl substituted with O(primary, secondary, or tertiary)C₁-C₈, OH, Cl, F, Br, I, ═O, —CN, NO₂,alkylamino, dialkylamino, alkarylamino, arylamino, alkylcarbonyl,aralkylcarbonyl, arylcarbonyl, carboxyl, alkylcarboxylate, alkylamido,dialkylamido, alkylureidoalkyl, alkylureidodialkyl, carbamoylalkyl,carbamoyldialkyl, alkylcarbamoyl, sulfonamidoalkyl, sulfonamidodialkyl,N-alkylsulfonamidoalkyl, N-alkylsulfonamidoalkyl,N-alkylsufonamidodialkyl, alkylamidosulfonate, dialkylamidosulfonate,alkylsulfinyl, alkylsulfonyl, CF₃, CF₂CF₃, CH₂F, CHF₂, CF₂CH₃, C(CH₃)₂F,OCF₃, OCHF₂, OCF₂CF₃ and OCH₂CF₃; C₂-C₈ alkenyl, C₂-C₈ alkynyl, whereinsaid alkenyl and alkynyl groups are optionally substituted with C₁-C₈alkyl, O (primary, secondary, or tertiary)C₁-C₈, OH, Cl, F, Br, I, ═O,—CN, NO₂, alkylamino, dialkylamino, alkarylamino, arylamino,alkylcarbonyl, aralkylcarbonyl, arylcarbonyl, carboxyl,alkylcarboxylate, alkylamido, dialkylamido, alkylureidoalkyl,alkylureidodialkyl, carbamoylalkyl, carbamoyldialkyl, alkylcarbamoyl,sulfonamidoalkyl, sulfonamidodialkyl, N-alkylsulfonamidoalkyl,N-alkylsulfonamidoalkyl, N-alkylsufonamidodialkyl, alkylamidosulfonate,dialkylamidosulfonate, alkylsulfinyl, alkylsulfonyl, CF₃, CF₂CF₃, CH₂F,CHF₂, CF₂CH₃, C(CH₃)₂F, OCF₃, OCHF₂, OCF₂CF₃ and OCH₂CF₃; C₃-C₁₀carbocycle, heterocycles, C₃-C₁₀ carbocyclylalkyl, heterocyclylalkyl andwherein said C₃-C₁₀ carbocycle, heterocycles, C₃-C₁₀ carbocyclylalkyl,and heterocyclylalkyl may be optionally substituted with one or moresubstituents selected from the group consisting of O (primary,secondary, or tertiary)C₁-C₈, OH, Cl, F, Br, I, ═O, —CN, NO₂,alkylamino, dialkylamino, alkarylamino, arylamino, alkylcarbonyl,aralkylcarbonyl, arylcarbonyl, carboxyl, alkylcarboxylate, alkylamido,dialkylamido, alkylureidoalkyl, alkylureidodialkyl, carbamoylalkyl,carbamoyldialkyl, alkylcarbamoyl, sulfonamidoalkyl, sulfonamidodialkyl,N-alkylsulfonamidoalkyl, N-alkylsulfonamido-alkyl,N-alkylsufonamidodialkyl, alkylamidosulfonate, dialkylamidosulfonate,alkylsulfinyl, alkylsulfonyl, CF₃, CF₂CF₃, CH₂F, CHF₂, CF₂CH₃, C(CH₃)₂F,OCF₃, OCF₂CF₃ and OCH₂CF₃, with the proviso that said C₃-C₁₀ carbocyclecan not be a phenyl group and C₃-C₁₀ carbocyclylalkyl can not be abenzyl group;

R³ is H or C₁₋₆ alkyl OR^(a), NR^(a)R^(a1), and S(O)_(p)R^(a);

R⁴ is selected from the group consisting of H, C₁₋₆ alkyl, OR^(a),NR^(a)R^(a1), and S(O)_(p)R^(a);

R⁵ at each occurrence is selected from the group consisting of C₁₋₁₀alkyl substituted with 0-2 R^(b), and C₁₋₈ alkyl substituted with 0-2R^(e);

R^(e) at each occurrence is selected from the group consisting of phenylsubstituted with 0-2 R^(b) and biphenyl substituted with 0-2 R^(b);

R⁶ at each occurrence is selected from the group consisting of phenyl,naphthyl,

C₁₋₁₀ alkyl-phenyl-C₁₋₆ alkyl-, C₃₋₁₁ cycloalkyl, C₁₋₆alkylcarbonyloxy-C₁₋₃ alkyl-,

C₁₋₆ alkoxycarbonyloxy-C₁₋₃ alkyl-, C₂₋₁₀ alkoxycarbonyl, C₃₋₆cycloalkylcarbonyloxy-C₁₋₃ alkyl-, C₃₋₆ cycloalkoxycarbonyloxy-C₁₋₃alkyl-,

C₃₋₆ cycloalkoxycarbonyl, phenoxycarbonyl, phenyloxycarbonyloxy-C₁₋₃alkyl-, phenylcarbonyloxy-C₁₋₃ alkyl-, C₁₋₆ alkoxy-C₁₋₆alkylcarbonyloxy-C₁₋₃ alkyl-, [5-(C₁-C₅alkyl)-1,3-dioxa-cyclopenten-2-one-yl]methyl,[5-(R^(a))-1,3-dioxa-cyclopenten-2-one-yl]methyl,(5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyl, —C₁₋₁₀ alkyl-NR⁷R^(7a),—CH(R⁸)OC(O)R⁹, and —CH(R⁸)OC(O)OR⁹;

alternatively, R⁴ and R⁶ can be taken together to form a 5-10 memberedring optionally substituted with R^(c);

R⁷ is selected from the group consisting of H, C₁₋₁₀ alkyl, C₂₋₆alkenyl, C₃₋₆ cycloalkyl-C₁₋₃ alkyl-, and phenyl-C₁₋₆ alkyl-;

R^(7a) is selected from the group consisting of H, C₁₋₁₀ alkyl, C₂₋₆alkenyl, C₃₋₆ cycloalkyl-C₁₋₃ alkyl-, and phenyl-C₁₋₆ alkyl-;

R⁸ is selected from the group consisting of H and C₁₋₄ linear alkyl;\

R⁹ is selected from the group consisting of H, C₁₋₈ alkyl substitutedwith 1-2 R^(f), C₃₋₈ cycloalkyl substituted with 1-2 R^(f), and phenylsubstituted with 0-2 R^(b);

R^(f) at each occurrence is selected from the group consisting of H,C₁₋₄ alkyl, C₃₋₈ cycloalkyl, C₁₋₅ alkoxy, and phenyl substituted with0-2 R^(b);

p at each occurrence is 0, 1, and 2; and

r at each occurrence is 0, or an integer from 1 to 10.

As defined above, Formula IA is intended to be the union of FormulaeI-VI and more specific embodiments as described below. Specifically,Formulae I-VI and other embodiments explicitly provide for 1, 2, and 3substituents to be present on ring A. Accordingly, Formula IA providesfor ring A to be substituted by 1, 2, or 3 R groups.

In another embodiment of the invention, compounds of formula I areprovided. As with compounds of formula IA, these compounds also possessutility as metalloprotease inhibitors, and preferably as matrixmetalloprotease inhibitors, sheddase inhibitors, and inhibitors of ADAMmetalloproteases. Compounds of formula IA, like those of formula I, areeither substituted carbocyclic or substituted heterocyclic compoundshaving the following general structure:

The variables in Formula I have the same meaning as those defined abovefor Formula IA. Specifically, R, R¹, and R² are defined identically.

In another embodiment of the invention compounds of the formula IIA andII are provided. This group of compounds, like those of formula I, alsopossess utility as metalloprotease inhibitors, and preferably as matrixmetalloprotease inhibitors, sheddase inhibitors, and inhibitors of ADAMmetalloproteases. Compounds of formula IIA and II, like those of formulaI, are either substituted carbocyclic or substituted heterocycliccompounds. Compounds of formula IIA have the following generalstructure:

wherein ring A is a 4-10 membered non-aromatic carbocycle or heterocyclecomprising carbon atoms, 0-1 carbonyl groups and from 0-2 ringheteroatoms selected from the group consisting of O, N, NR, providedthat ring A contains other than a O—O bond. Variable n′ is 1 or 2. Asubset of compounds of Formula IIA conform to Formula II, which has thefollowing structure:

The A-ring substituent groups R, R¹, P, and Z are described in fulldetail below with regard to the description of the preferredembodiments; for the sake of summary suffice it to say that each of thesubstituent groups is defined as a more preferred subset of thecorresponding substituent group as defined for the formula I compounds.

In a further preferred embodiment the invention provides for cyclichydroxamate compounds and/or derivatives possessing potentmetalloprotease inhibitory activity, these compounds having thestructural formula IIIA or IVA:

wherein ring A is a 5-7 membered non-aromatic carbocycle or heterocyclecomprising carbon atoms, 0-1 carbonyl groups and from 0-2 ringheteroatoms selected from the group consisting of O, N, NR, providedthat ring A contains other than a O—O bond. Variable n′ is 1 or 2.Subsets of compounds according to Formulae IIIA and IVA are those ofFormulae III and IV, respectively. The structures of these compounds areshown below:

The A-ring substituent groups R, R¹, and P are described in full detailbelow with regard to the description of the preferred embodiments; forthe sake of summary suffice it to say that each of the substituentgroups is defined as a more preferred subset of the correspondingsubstituent group as defined for the formula I compounds.

In another preferred embodiment the invention provides for cyclichydroxamate compounds and/or derivatives possessing potentmetalloprotease inhibitory activity, these compounds having thestructural formulas VA and VIA

Variable n′ is 1 or 2. A subset of compounds according for Formulae VAand VIA are those of Formulae V and VI, which have the followingstructures:

The invention also provides a method for treating a disease associatedwith unwanted metalloprotease activity in a mammalian subject, themethod comprising administering to said mammal in need thereof, aneffective amount of a metalloprotease inhibitor compound of formulae I,IA, II, IIA, III, IIIA, IV, IVA, V, VA, VI, or VIA.

The instant invention further provides a method for treating a diseasesmodulated by metalloproteases in a mammalian subject, wherein thedisease is selected from the group consisting of arthritis, cancer,cardiovascular disorders, skin disorders, inflammation and allergicconditions by administering to said mammal in need of such treatment, aneffective amount of a metalloprotease inhibitor compound of formulae I,IA, II, IIA, III, IIIA, IV, IVA, V, VA, VI, or VIA.

The present invention also provides a method of inhibiting pathologicalchanges mediated by elevated levels of matrix metalloproteases, such asMMP 12, in mammals comprising administering to said mammal in needthereof a therapeutically effective amount of a matrix metalloproteaseinhibiting compound of formulae I, IA, II, IIA, III, IIIA, IV, IVA, V,VA, VI, or VIA.

The invention further relates to a method for treating a diseaseassociated with unwanted sheddase activity, such as Her-2 sheddase,other growth factor sheddase and cytokine sheddases, in a mammaliansubject, the method comprising administering to said mammal in needthereof, an effective amount of a sheddase inhibitor compound offormulae I, IA, II, IIA, III, IIIA, IV, IVA, V, VA, VI, or VIA.

The instant invention also provides a method for treating a diseaseassociated with unwanted TNF-α converting enzyme and ADAM 10 activity ina mammalian subject, the method comprising administering to said mammalin need thereof, an effective amount of a TNF-α converting enzymeinhibitor compound of formulae I, IA, II, IIA, III, IIIA, IV, IVA, V,VA, VI, or VIA.

Additionally, the invention also provides a pharmaceutical compositionfor use in therapy, comprising a compound according to the invention ina therapeutically effective amount, and at least apharmaceutically-acceptable diluent or carrier, and other optionalexcipients necessitated by the dosage form and the intended route ofadministration.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The instant invention provides new compounds and pharmaceuticalcompositions of matter for treating pathological conditions which areassociated with the rapid unregulated breakdown of extracellular matrixtissue by MMPs including MMP 12 and MMP 13. Some of these conditionsinclude rheumatoid arthritis, osteoarthritis, septic arthritis, corneal,epidermal or gastric ulceration; periodontal disease, proteinuria,coronary thrombosis associated with atherosclerotic plaque rupture andbone disease. The new compounds of the invention are also useful fortreating tumor metastasis and angiogenesis which also appears to bedependent on MMP activity. Also, since the cycle of tissue damage andresponse is associated with a worsening of the disease state, limitingMMP-induced tissue damage due to elevated levels of the proteinases withthe specific inhibitors of the instant invention is a generally usefultherapeutic approach to many of these debilitating diseases. Thecompounds of the invention are also inhibitors TNFα converting enzymeand sheddases including Her2 sheddase and HB-EGF sheddase and othergrowth factor and cytokine sheddase.

The instant invention also provides novel compounds, novel compositions,methods of their use and methods of their manufacture, such compoundsgenerally pharmacologically useful as agents in those disease statesalleviated by the inhibition or antagonism of matrix metalloproteases,metalloproteases, ADAMs, ADAM-TS and/or tumor necrosis factor-α (TNF),which pathologically involve aberrant extracellular matrix degradation,shedding of cell surface protein ectodomains, and/or TNF synthesis, suchdisease states including arthritis, tumor metastasis and diabetes. Theaforementioned pharmacologic activities are useful in the treatment ofmammals.

More specifically, the instant invention relates to new anti-cancer,anti-inflammatory and immunomodulatory cyclic hydroxamate bioactivecompounds and pharmaceutical compositions thereof that act viaantagonism of MMPs, ADAMs, ADAMTS, sheddase such as Her2 sheddase andtherefore leading to new therapeutic modalities.

The present invention also relates to compounds that inhibitmetalloproteases such as MMP12, ADAMs family metalloproteases includingTNF α-convertase, Adam-10 and related sheddases such as Her2 sheddase,heparin-binding EGF sheddase and are therefore useful in the treatmentof mammals having disease states alleviated by the inhibition of suchmetalloprotease activity.

The instant invention also relates to inhibitors of ADAMmetalloproteases which are responsible for the release or shedding ofsoluble receptors (for example, CD30 and receptors for TNF), adhesionmolecules (for example, L-selectin, ICAM-1, fibronectin), growth factorsand cytokines (for example Fas ligand, TGF-α, EGF, HB-EGF, SCF IL-6,IL-1, TSH and M-CSF), and growth factor receptors (for example EGFRfamily members, such as Her-2 and Her-4, which have been implicated inthe pathogenesis of different types of cancer.)

More in particular, the present invention provides new compounds havingthe formula IA:

its enantiomers, diastereomers, enantiomerically enriched mixtures,racemic mixtures thereof, prodrugs, crystalline forms, non-crystallineforms, amorphous forms thereof, solvates thereof, metabolites thereof,and pharmaceutically acceptable salts, wherein:

ring A is a 3-13 membered carbocycle or heterocycle comprising carbonatoms, 0-3 carbonyl groups, 0-4 double bonds, and from 0-4 ringheteroatoms selected from the group consisting of O, N, NR, andS(O)_(p), provided that ring A contains other than a S—S, O—O, or S—Obond;

n′ is 1, 2, or 3;

Z is selected from the group consisting of —COR⁵, —CO₂H, —CH₂CO₂H,—CO₂R⁶,

—CONHOH, —CONHOR⁵, —CON(R⁶)OH, —CONHOR⁶, —NHR^(a), —N(OH)C(O)R⁵,—N(OH)CHO, —SH, —CH₂SH, —S(O)(═NH)R^(a), —SN₂H₂R^(a), —PO(OR^(g))₂,—PO(OH)NHR^(a),

R^(g) is independently selected from the group consisting of H,CH₂OCOR^(a), P is -D-E-G-Q-L-T-X-Y, wherein

D is absent or is selected from the group consisting of O, NR^(a1),C(O), C(O)O, OC(O), C(O)NR^(a1), NR^(a1)C(O), OC(O)O, OC(O)NR^(a1),NR^(a1)C(O)O, NR^(a1)C(O)NR^(a1), S(O)_(p), S(O)_(p)NR^(a1), NR^(a1)S(O)_(p), and NR^(a1)SO₂NR^(a1);

E is absent or is selected from the group consisting of C₁₋₁₀alkylene,C₂₋₁₀ alkenylene, and

C₂₋₁₀ alkynylene;

G is absent or is selected from the group consisting of O, NR^(a1),S(O)_(p), and C(O);

Q is absent or is selected from the group consisting of a C₃₋₁₃carbocycle substituted with 0-5 R^(b), and a 5-14 membered heterocyclecomprising carbon atoms and 1-4 heteroatoms selected from the groupconsisting of N, O, and S(O)_(p), and said heterocycle being substitutedwith 0-5 R^(b);

L is absent or is selected from the group consisting of O, NR^(a1),C(O), C(O)O, OC(O), C(O)NR^(a1), NR^(a1)C(O), OC(O)O, OC(O)NR^(a1),NR^(a1)C(O)O, NR^(a1)C(O)NR^(a1), S(O)_(p), S(O)_(p)NR^(a1),NR^(a1)S(O)_(p), and NR^(a1)SO₂NR^(a1);

T is absent or is selected from the group consisting of C₁₋₁₀ alkylene,C₂₋₁₀ alkenylene, and C₂₋₁₀ alkynylene;

X is absent or is selected from the group consisting of O, NR^(a1),S(O)_(p), and C(O);

Y is selected from the group consisting of H, a C₃₋₁₃ carbocyclesubstituted with 0-5 R^(c) and a 5-14 membered heterocycle comprisingcarbon atoms and 1-4 heteroatoms selected from the group consisting ofN, O, and S(O)_(p), and said heterocycle being substituted with 0-5R^(c);

provided that D, E, G, Q, L, T, X and Y do not combine to form a N—N,N—O, O—N, O—O, S(O)_(p)—O, O—S(O)_(p) or S(O)_(p)—S(O)_(p) group;

R, at each occurrence, is independently selected from (C₁₋₁₀ alkylenesubstituted with

1-3 R^(b1))-M, (C₂₋₁₀ alkenylene substituted with 1-3 R^(b1))-M, (C₂₋₁₀alkynylene substituted with 1-3 R^(b1))-M, OH, Cl, F, Br, I, —CN, NO₂,CF₃, CF₂CF₃, CH₂F, CHF₂, CF₂CH₃, C(CH₃)₂F, OCF₃, OCF₂CF₃, OCHF₂,O(CR^(d)R^(d1))_(r)-M, NR^(a)(CR^(d)R^(d1))_(r)-M,OC(O)(CR^(d)R^(d1))_(r)-M, NR^(a)C(O)(CR^(d)R^(d1))_(r)-M,OC(O)O(CR^(d)R^(d1))_(r)-M, OC(O)NR^(a)(CR^(d)R^(d1))_(r)-M,NR^(a)C(O)O(CR^(d)R^(d1))_(r)-M, NR^(a)C(O)NR^(a1)(CR^(d)R^(d1))_(r)-M,S(O)_(p)(CR^(d)R^(d1))_(r)-M, S(O)₂NR^(a)(CR^(d)R^(d1))_(r)-M,NR^(a)S(O)₂(CR^(d)R^(d1))_(r)-M, andNR^(a)S(O)₂NR^(a1)(CR^(d)R^(d1))_(r)-M, (CR^(d)R^(d1))_(r)P(O)(OR^(a))₂,(CR^(d)R^(d1))_(r)P(O)(OR^(a))(NR^(d)R^(d1)),(CR^(d)R^(d1))_(r)P(O)(NR^(a)R^(a1))₂, (CR^(d)R^(d1))_(r)OP(O)(OR^(a))₂,(CR^(d)R^(d1))_(r)OP(O)(OR^(a))(NR^(a)R^(a1)),(CR^(d)R^(d1))_(r)OP(O)(NR^(a)R^(a1))₂,(CR^(d)R^(d1))_(r)NR^(a)P(O)(OR^(a))₂,(CR^(d)R^(d1))_(r)NR^(a)P(O)(OR^(a))(NR^(a)R^(a1)),(CR^(d)R^(d1))_(r)NR^(a)P(O)(NR^(a)R^(a1))₂; C(═NR^(a))NR^(a1)R^(a2);C(═CR^(d)R^(d1))NR^(a1)R^(a2) a C₃₋₁₃ carbocycle substituted with 0-5R^(d), and a 5-14 membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from the group consisting of N, O, S(O)_(p) andsaid heterocycle being substituted with 0-5 R^(d);

alternatively, two R, together with a carbon atom on A, form the groupC_(A)═CR^(d)R^(d1), where the atom C_(A) is said atom on A;

M is selected from the group consisting of H, C₂₋₁₀ alkenylenesubstituted with 0-3 R^(b1), C₂₋₁₀ alkynylene substituted with 0-3R^(b1), OR^(a), Cl, F, Br, I, —CN, NO₂, NR^(a)R^(a1), C(O)R^(a),C(O)OR^(a) C(O)NR^(a)R^(a1), R^(a)NC(O)NR^(a)R^(a1), OC(O)NR^(a)R^(a1),NR^(a)C(O)OR^(a), NR^(a)C(O)R^(a), S(O)₂NR^(a)R^(a1), NR^(a)S(O)₂R^(a2),NR^(a)S(O)₂NR^(a)R^(a1), OS(O)₂NR^(a)R^(a1), S(O)_(p)R^(a2), CF₃,CF₂CF₃, CH₂F, CHF₂, CF₂CH₃, C(CH₃)₂F, OCF₃, OCHF₂, a C₃₋₁₃ carbocyclesubstituted with 0-5 R^(d), and a 5-14 membered heterocycle comprisingcarbon atoms and 1-4 heteroatoms selected from the group consisting ofN, O, S(O)_(p) and said heterocycle being substituted with 0-5 R^(d);

alternatively, R, at each occurrence, is independently selected fromC₁₋₁₀ alkylene-M¹,

C₂₋₁₀ alkenylene-M¹, C₂₋₁₀ alkynylene-M¹,(CR^(d)R^(d1))_(r)O(CR^(d)R^(d1))_(r)-M¹,

(CR^(d)R^(d1))_(r)NR^(a)(CR^(d)R^(d1))_(r)-M¹,(CR^(d)R^(d1))_(r)C(O)(CR^(d)R^(d1))_(r)-M¹,

(CR^(d)R^(d1))_(r)C(O)O(CR^(d)R^(d1))_(r)(CR^(d)R^(d1))_(r)OC(O)(CR^(d)R^(d1))_(r)-M¹,

(CR^(d)R^(d1))^(r)C(O)NR^(a)(CR^(d)R^(d1))_(r)-M¹,(CR^(d)R^(d1))_(r)NR^(a)C(O)(CR^(d)R^(d1))_(r)-M¹,

(CR^(d)R^(d1))_(r)OC(O)O(CR^(d)R^(d1))_(r)-M¹,(CR^(d)R^(d1))_(r)OC(O)NR^(a)(CR^(d)R^(d1))_(r)-M¹,

(CR^(d)R^(d1))_(r)NR^(a)C(O)O(CR^(d)R^(d1))_(r)-M¹,(CR^(d)R^(d1))_(r)NR^(a)C(O)NR^(a1)(CR^(d)R^(d1))_(r)-M¹,(CR^(d)R^(d1))_(r)S(O)_(p)(CR^(d)R^(d1))_(r)-M¹,(CR^(d)R^(d1))_(r)S(O)₂NR^(a)(CR^(d)R^(d1))_(r)-M¹,(CR^(d)R^(d1))_(r)NR^(a)S(O)₂(CR^(d)R^(d1))_(r)-M¹, and(CR^(d)R^(d1))_(r)NR^(a)S(O)₂NR^(a1)(CR^(d)R^(d1))_(r)-M¹;

M¹ is selected from the group consisting of OR^(a), Cl, F, Br, I, —CN,NO₂, NR^(a)R^(a1), C(O)R^(a), C(O)OR^(a), C(O)NR^(a)R^(a1),R^(a)NC(O)NR^(a)R^(a1), OC(O)NR^(a)R^(a1), R^(a)NC(O)OR^(a),S(O)₂NR^(a)R^(a1), NR^(a)S(O)₂R^(a2), NR^(a)S(O)₂NR^(a)R^(a1),OS(O)₂NR^(a)R^(a1), S(O)_(p)R^(a2), CF₃, CF₂CF₃, CH₂F, CHF₂, CF₂CH₃,C(CH₃)₂F, OCF₃, OCF₂CF₃, and a 5-14 membered non-aromatic heterocyclecomprising carbon atoms and 1-4 heteroatoms selected from the groupconsisting of N, O, S(O)_(p) and said heterocycle being substituted with0-5 R^(d); a C₃-C₁₃ carbocycle, C₄-C₁₄ heterocycle and wherein saidC₃-C₁₃ carbocycle and C₄-C₁₄ heterocycle are substituted with 1-3 R^(h),and CF₃, CF₂CF₃, CH₂F, CHF₂, CF₂CH₃, C(CH₃)₂F, OCF₃, OCHF₂, OCF₂CF₃ andOCH₂CF₃;

alternatively, when two R groups are attached to adjacent ring A atoms,together with the atoms to which they are attached they may form a 3-8membered saturated, partially saturated or unsaturated ring comprised ofcarbon atoms and 0-3 heteroatoms selected from the group consisting ofN, NR^(a), O, and S(O)_(p), wherein said ring may be benezene-fusedand/or substituted with R^(d); alternatively, when two R groups areattached to the same ring A carbon, together with the carbon to whichthey are attached they may form a 3-8 membered saturated, partiallysaturated or unsaturated spiro-ring comprised of carbon atoms and 0-3heteroatoms selected from the group consisting of N, NR^(a), O, andS(O)_(p), wherein said spiro-ring may be benezene-fused and/orsubstituted with R^(d);

provided that either two or more R or M, M¹ and the atom to which theyare attached do not combine to form a N—N, N—O, O—N, O—O, N-halogen,O-halogen, S-halogen, S(O)_(p)—O, O—S(O)_(p), S(O)_(p)—S(O)_(p) group,or C(O)F, C(O)Cl, C(O)Br, or C(O)I reactive group;

R^(a), R^(a1), and R^(a2) at each occurrence are independently selectedfrom the group consisting of H, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈alkynyl, wherein said alkyl, alkenyl and alkynyl groups are optionallysubstituted with O (primary, secondary, or tertiary)C₁-C₈, OH, Cl, F,Br, I, ═O, —CN, NO₂, alkylamino, dialkylamino, alkarylamino, arylamino,alkylcarbonyl, aralkylcarbonyl, arylcarbonyl, carboxyl,alkylcarboxylate, alkylamido, dialkylamido, alkylureidoalkyl,alkylureidodialkyl, carbamoylalkyl, carbamoyldialkyl, alkylcarbamoyl,sulfonamidoalkyl, sulfonamidodialkyl, N-alkylsulfonamidoalkyl,N-alkylsulfonamidoalkyl, N-alkylsufonamidodialkyl, alkylamidosulfonate,dialkylamidosulfonate, alkylsulfinyl, alkylsulfonyl, CF₃, CF₂CF₃, CH₂F,CHF₂, CF₂CH₃, C(CH₃)₂F, OCF₃, OCF₂CF₃ and OCH₂CF₃; C₃-C₁₀ carbocycle,heterocycles, C₃-C₁₀ carbocyclylalkyl, heterocyclylalkyl and whereinsaid C₃-C₁₀ carbocycle, heterocycles, C₃-C₁₀ carbocyclylalkyl, andheterocyclylalkyl may be optionally substituted with one or moresubstituents selected from the group consisting of C₁-C₈ alkyl, O(primary, secondary, or tertiary)C₁-C₈, OH, Cl, F, Br, I, ═O, —CN, NO₂,alkylamino, dialkylamino, alkarylamino, arylamino, alkylcarbonyl,aralkylcarbonyl, arylcarbonyl, carboxyl, alkylcarboxylate, alkylamido,dialkylamido, alkylureidoalkyl, alkylureidodialkyl, carbamoylalkyl,carbamoyldialkyl, alkylcarbamoyl, sulfonamidoalkyl, sulfonamidodialkyl,N-alkylsulfonamidoalkyl, N-alkylsulfonamido-alkyl,N-alkylsufonamidodialkyl, alkylamidosulfonate, dialkylamidosulfonate,alkylsulfinyl, alkylsulfonyl, CF₃, CF₂CF₃, CH₂F, CHF₂, CF₂CH₃, C(CH₃)₂F,OCF₃, OCF₂CF₃ and OCH₂CF₃;

alternatively, R^(a) and R^(a1) taken together with the nitrogen towhich they are attached form a 4 to 8 membered ring containing from 0-1additional heteroatoms selected from the group consisting of N, O, andS, wherein said ring may be substituted with R^(d);

R^(b) at each occurrence is independently selected from the groupconsisting of C₁₋₆ alkyl optionally substituted with R^(c1), O (primary,secondary, or tertiary)C₁-C₈, OH, Cl, F, Br, I, ═O, —CN, NO₂,NR^(a)R^(a1), C(O)R^(a), C(O)OR^(a), C(O)NR^(a)R^(a1),R^(a)NC(O)NR^(a)R^(a), OC(O)NR^(a)R^(a1), R^(a)NC(O)OR^(a1),S(O)₂NR^(a)R^(a1), NR^(a)S(O)₂R^(a2), NR^(a)S(O)₂NR^(a)R^(a1),OS(O)₂NR^(a)R^(a1), S(O)_(p)R^(a2), CF₃, CF₂CF₃, CH₂F, CHF₂, CF₂CH₃,C(CH₃)₂F, OCF₃, OCHF₂, OCF₂CF₃ and OCH₂CF₃; C₃₋₁₀ carbocyclic residue,and a 5-14 membered heterocyclic system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S, C₃-C₁₀carbocyclyl(C₁₋₈)alkyl, and 5-14 heterocyclyl-(C₁₋₈)alkyl and said C₃₋₁₀carbocyclic residue, heterocyclic system,

C₃-C₁₀ carbocyclyl(C₁₋₈)alkyl, and 5-14 heterocyclyl(C₁₋₈)alkyl areoptionally substituted with R^(c1);

R^(b1) at each occurrence is independently selected from the groupconsisting of OR^(a), F, ═O, —CN, NO₂, NR^(a)R^(a1) and S(O)_(p)R^(a);

R^(c) at each occurrence is independently selected from the groupconsisting of C₁₋₆ alkyl optionally substituted with R^(c1), OR^(a), Cl,F, Br, I, ═O, —CN, NO₂, NR^(a)R^(a1), C(O)R^(a), C(O)OR^(a),C(O)NR^(a)R^(a1), R^(a)NC(O)NR^(a)R^(a), OC(O)NR^(a)R^(a1),R^(a)NC(O)OR^(a1), S(O)₂NR^(a)R^(a1), NR^(a)S(O)₂R^(a2),NR^(a)S(O)₂NR^(a)R^(a1), OS(O)₂NR^(a)R^(a1), S(O)_(p)R^(a2), CF₃,CF₂CF₃, CH₂F, CHF₂, CF₂CH₃, C(CH₃)₂F, OCF₃, OCHF₂, OCF₂CF₃ and OCH₂CF₃;a C₃₋₁₀ carbocyclic residue, and a 5-14 membered heterocyclic systemcontaining from 1-4 heteroatoms selected from the group consisting of N,O, and S, C₃-C₁₀ carbocyclyl(C₁₋₈)alkyl, and 5-14heterocyclyl(C₁₋₈)alkyl; said C₃₋₁₀ carbocyclic residue, heterocyclicsystem C₃-C₁₀ carbocyclyl(C₁₋₈)alkyl, and 5-14 heterocyclyl(C₁₋₈)alkylare optionally substituted with R^(c1).

R^(c1) at each occurrence is independently selected from the groupconsisting of C₁₋₆ alkyl, OR^(a), Cl, F, Br, I, ═O, —CN, NO₂,NR^(a)R^(a1), C(O)R^(a), C(O)OR^(a), C(O)NR^(a)R^(a1),OC(O)NR^(a)R^(a1), R^(a)NC(O)OR^(a), S(O)₂NR^(a)R^(a1),NR^(a)S(O)₂R^(a2), NR^(a)S(O)₂NR^(a)R^(a1), S(O)_(p)R^(a2), CF₃, andCF₂CF₃, CH₂F, and CHF₂;

R^(d) at each occurrence is independently selected from the groupconsisting of H, C₁₋₆ alkyl optionally substituted with R^(c1), OR^(a),Cl, F, Br, I, ═O, —CN, NO₂, NR^(a)R^(a1), C(O)R^(a), C(O)OR^(a),C(O)NR^(a)R^(a1), R^(a)NC(O)NR^(a)R^(a), OC(O)NR^(a)R^(a1),R^(a)NC(O)OR^(a1), S(O)₂NR^(a)NR^(a)S(O)₂R^(a2),NR^(a)S(O)₂NR^(a)R^(a1), OS(O)₂NR^(a)R^(a1), S(O)_(p)R^(a2), CF₃,CF₂CF₃, CH₂F, CHF₂, CF₂CH₃, C(CH₃)₂F, OCF₃, OCHF₂, OCF₂CF₃ and OCH₂CF₃;C₃₋₁₀ carbocyclic residue, and a 5-14 membered heterocyclic systemcontaining from 1-4 heteroatoms selected from the group consisting of N,O, and S, C₃-C₁₀ carbocyclyl(C₁₋₈)alkyl, and 5-14heterocyclyl(C₁₋₈)alkyl; said C₃₋₁₀ carbocyclic residue, heterocyclicsystem C₃-C₁₀ carbocyclyl(C₁₋₈)alkyl, and 5-14 heterocyclyl(C₁₋₈)alkyloptionally substituted with R^(c1).

R^(d1) at each occurrence is independently selected from the groupconsisting of H, C₁₋₆ alkyl optionally substituted with R^(c1), OR^(a),Cl, F, Br, I, ═O, —CN, NO₂, NR^(a)R^(a1), C(O)R^(a), C(O)OR^(a),C(O)NR^(a)R^(a1), R^(a)NC(O)NR^(a)R^(a), OC(O)NR^(a)R^(a1),R^(a)NC(O)OR^(a1), S(O)₂NR^(a)R^(a1), NR^(a)S(O)₂R^(a2),NR^(a)S(O)₂NR^(a)R^(a1), OS(O)₂NR^(a)R^(a1), S(O)_(p)R^(a2), CF₃,CF₂CF₃, CH₂F, CHF₂, CF₂CH₃, C(CH₃)₂F, OCF₃, OCHF₂, OCF₂CF₃ and OCH₂CF₃;C₃₋₁₀ carbocyclic residue, and a 5-14 membered heterocyclic systemcontaining from 1-4 heteroatoms selected from the group consisting of N,O, and S, C₃-C₁₀ carbocyclyl(C₁₋₈)alkyl, and 5-14heterocyclyl(C₁₋₈)alkyl; said C₃₋₁₀ carbocyclic residue, heterocyclicsystem C₃-C₁₀ carbocyclyl(C₁₋₈)alkyl, and 5-14 heterocyclyl(C₁₋₈)alkyloptionally substituted with R.

alternatively, R^(d) and R^(d1) taken together with the atom to whichthey are attached form a 4 to 8 membered ring containing from 0-1heteroatoms selected from the group consisting of N, O, and S, whereinsaid ring may be substituted with R^(d);

R^(h) at each occurrence is independently selected from the groupconsisting of OR^(j), NR^(j)R^(a), COR^(j), C(O)OR^(j), C(O)NR^(j)R^(a),NR^(a)C(O)NR^(j)R^(a1), OC(O)NR^(j)R^(a), S(O)_(p)NR^(j)R^(a1),NR^(a)S(O)pR^(j), NR^(a)S(O)pNR^(j)R^(a), C₁₋₆ alkyl substituted withR^(c).

R^(j) at each occurrence is independently selected from the groupconsisting of CF₃, CH₂F, CHF₂, CF₂CF₃, C1-C8 alkyl substituted with O(primary, secondary, or tertiary)C₁-C₈, OH, Cl, F, Br, I, ═O, —CN, NO₂,alkylamino, dialkylamino, alkarylamino, arylamino, alkylcarbonyl,aralkylcarbonyl, arylcarbonyl, carboxyl, alkylcarboxylate, alkylamido,dialkylamido, alkylureidoalkyl, alkylureidodialkyl, carbamoylalkyl,carbamoyldialkyl, alkylcarbamoyl, sulfonamidoalkyl, sulfonamidodialkyl,N-alkylsulfonamidoalkyl, N-alkylsulfonamidoalkyl,N-alkylsufonamidodialkyl, alkylamidosulfonate, dialkylamidosulfonate,alkylsulfinyl, alkylsulfonyl, CF₃, CF₂CF₃, CH₂F, CHF₂, CF₂CH₃, C(CH₃)₂F,OCF₃, OCHF₂, OCF₂CF₃ and OCH₂CF₃; C₂-C₈ alkenyl, C₂-C₈ alkynyl, whereinsaid alkenyl and alkynyl groups are optionally substituted with C₁-C₈alkyl, O (primary, secondary, or tertiary)C₁-C₈, OH, Cl, F, Br, I, ═O,—CN, NO₂, alkylamino, dialkylamino, alkarylamino, arylamino,alkylcarbonyl, aralkylcarbonyl, arylcarbonyl, carboxyl,alkylcarboxylate, alkylamido, dialkylamido, alkylureidoalkyl,alkylureidodialkyl, carbamoylalkyl, carbamoyldialkyl, alkylcarbamoyl,sulfonamidoalkyl, sulfonamidodialkyl, N-alkylsulfonamidoalkyl,N-alkylsulfonamidoalkyl, N-alkylsufonamidodialkyl, alkylamidosulfonate,dialkylamidosulfonate, alkylsulfinyl, alkylsulfonyl, CF₃, CF₂CF₃, CH₂F,CHF₂, CF₂CH₃, C(CH₃)₂F, OCF₃, OCHF₂, OCF₂CF₃ and OCH₂CF₃; C₃-C₁₀carbocycle, heterocycles, C₃-C₁₀ carbocyclylalkyl, heterocyclylalkyl andwherein said C₃-C₁₀ carbocycle, heterocycles, C₃-C₁₀ carbocyclylalkyl,and heterocyclylalkyl may be optionally substituted with one or moresubstituents selected from the group consisting of O (primary,secondary, or tertiary)C₁-C₈, OH, Cl, F, Br, I, ═O, —CN, NO₂,alkylamino, dialkylamino, alkarylamino, arylamino, alkylcarbonyl,aralkylcarbonyl, arylcarbonyl, carboxyl, alkylcarboxylate, alkylamido,dialkylamido, alkylureidoalkyl, alkylureidodialkyl, carbamoylalkyl,carbamoyldialkyl, alkylcarbamoyl, sulfonamidoalkyl, sulfonamidodialkyl,N-alkylsulfonamidoalkyl, N-alkylsulfonamido-alkyl,N-alkylsufonamidodialkyl, alkylamidosulfonate, dialkylamidosulfonate,alkylsulfinyl, alkylsulfonyl, CF₃, CF₂CF₃,

CH₂F, CHF₂, CF₂CH₃, C(CH₃)₂F, OCF₃, OCF₂CF₃ and OCH₂CF₃, with theproviso that said C₃-C₁₀ carbocycle can not be a phenyl group and C₃-C₁₀carbocyclylalkyl can not be a benzyl group;

R³ is H or C₁₋₆ alkyl OR^(a), NR^(a)R^(a1), and S(O)_(p)R^(a);

R⁴ is selected from the group consisting of H, C₁₋₆ alkyl, OR^(a),NR^(a)R^(a1), and S(O)_(p)R^(a);

R⁵ at each occurrence is selected from the group consisting of C₁₋₁₀alkyl substituted with 0-2 R^(b), and C₁₋₈ alkyl substituted with 0-2R^(e);

R^(e) at each occurrence is selected from the group consisting of phenylsubstituted with 0-2 R^(b) and biphenyl substituted with 0-2 R^(b);

R⁶ at each occurrence is selected from the group consisting of phenyl,naphthyl,

C₁₋₁₀ alkyl-phenyl-C₁₋₆ alkyl-, C₃₋₁₁ cycloalkyl, C₁₋₆alkylcarbonyloxy-C₁₋₃ alkyl-, C₁₋₆ alkoxycarbonyloxy-C₁₋₃ alkyl-, C₂₋₁₀alkoxycarbonyl, C₃₋₆ cycloalkylcarbonyloxy-C₁₋₃ alkyl-, C₃₋₆cycloalkoxycarbonyloxy-C₁₋₃ alkyl-,

C₃₋₆ cycloalkoxycarbonyl, phenoxycarbonyl, phenyloxycarbonyloxy-C₁₋₃alkyl-, phenylcarbonyloxy-C₁₋₃ alkyl-, C₁₋₆ alkoxy-C₁₋₆alkylcarbonyloxy-C₁₋₃ alkyl-, [5-(C₁-C₅alkyl)-1,3-dioxa-cyclopenten-2-one-yl]methyl,[5-(R^(a))-1,3-dioxa-cyclopenten-2-one-yl]methyl,(5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyl, —C₁₋₁₀ alkyl-NR⁷R^(7a),—CH(R⁸)OC(O)R⁹, and —CH(R⁸)OC(O)OR⁹;

alternatively, R⁴ and R⁶ can be taken together to form a 5-10 memberedring optionally substituted with R^(c);

R⁷ is selected from the group consisting of H, C₁₋₁₀ alkyl, C₂₋₆alkenyl, C₃₋₆ cycloalkyl-C₁₋₃ alkyl-, and phenyl-C₁₋₆ alkyl-;

R^(7a) is selected from the group consisting of H, C₁₋₁₀ alkyl, C₂₋₆alkenyl, C₃₋₆ cycloalkyl-C₁₋₃ alkyl-, and phenyl-C₁₋₆ alkyl-;

R⁸ is selected from the group consisting of H and C₁₋₄ linear alkyl;

R⁹ is selected from the group consisting of H, C₁₋₈ alkyl substitutedwith 1-2 R^(f), C₃₋₈ cycloalkyl substituted with 1-2 R^(f), and phenylsubstituted with 0-2 R^(b);

R^(f) at each occurrence is selected from the group consisting of H,C₁₋₄ alkyl, C₃₋₈ cycloalkyl, C₁₋₅ alkoxy, and phenyl substituted with0-2 R^(b);

p at each occurrence is 0, 1, and 2; and

r at each occurrence is 0, or an integer from 1 to 10.

In a preferred embodiment, the present invention provides for a novelclass of compounds according to the formula IIA:

wherein ring A is a 4-10 membered non-aromatic carbocycle or heterocyclecomprising carbon atoms, 0-1 carbonyl groups and from 0-2 ringheteroatoms selected from the group consisting of O, N, NR, providedthat ring A contains other than a O—O bond;

n′ is 1 or 2;

Z is selected from the group consisting of —CO₂H, —CH₂CO₂H, —CONHOH,—CONHOR⁵, —NHR^(a), —N(OH)C(O)R⁵, —N(OH)CHO, —SH, —CH₂SH, and

P is D-E-G-Q-L-T-X-Y, wherein

D is absent or is selected from the group consisting of O, NR^(a1),C(O), C(O)O, OC(O), C(O)NR^(a1), NR^(a1)C(O), OC(O)NR^(a1),NR^(a1)C(O)O, NR^(a1)C(O)NR^(a1), S(O)_(p), S(O)_(p)NR^(a1), andNR^(a1)S(O)_(p);

E is absent or is selected from the group consisting of C₁₋₁₀alkylene,C₂₋₁₀ alkenylene, and

C₂₋₁₀ alkynylene;

G is absent or is selected from the group consisting of O, NR^(a1),S(O)_(p), and C(O);

Q is absent or is selected from the group consisting of a C₃₋₁₀carbocycle substituted with 0-5 R^(b), and a 5-10 membered heterocyclecomprising carbon atoms and 1-4 heteroatoms selected from the groupconsisting of N, O, and S(O)_(p), and said heterocycle being substitutedwith 0-5 R^(b);

L is absent or is selected from the group consisting of O, NR^(a1),C(O), C(O)O, OC(O), C(O)NR^(a1), NR^(a1)C(O), OC(O)NR^(a1),NR^(a1)C(O)O, S(O)_(p), S(O)_(p)NR^(a1), and NR^(a1)S(O)_(p);

T is absent or is selected from the group consisting of C₁₋₁₀ alkylene,C₂₋₁₀ alkenylene, and C₂₋₁₀ alkynylene;

X is absent or is selected from the group consisting of O, NR^(a1),S(O)_(p), and C(O);

Y is selected from the group consisting of H, a C₃₋₁₀ carbocyclesubstituted with 0-5 R^(c) and a 5-10 membered heterocycle comprisingcarbon atoms and 1-4 heteroatoms selected from the group consisting ofN, O, and S(O)_(p), and said heterocycle being substituted with 0-5R^(c);

provided that D, E, G, Q, L, T, X and Y do not combine to form a N—N,N—O, O—N, O—O, S(O)_(p)—O, O—S(O)_(p) or S(O)_(p)—S(O)_(p) group;

R, at each occurrence, is independently selected from (C₁₋₁₀ alkylenesubstituted with

1-3 R^(b1))-M, (C₂₋₁₀ alkenylene substituted with 1-3 R^(b1))-M, (C₂₋₁₀alkynylene substituted with 1-3 R^(b1))-M, OH, Cl, F, Cl, —CN, NO₂, CF₃,CF₂CF₃, CH₂F, CHF₂, CF₂CH₃, C(CH₃)₂F, OCF₃, OCHF₂,O(CR^(d)R^(d1))_(r)-M, NR^(a)(CR^(d)R^(d1))_(r)-M,OC(O)(CR^(d)R^(d1))_(r)-M, NR^(a)C(O)(CR^(d)R^(d1))_(r)-M,OC(O)O(CR^(d)R^(d1))_(r)-M, OC(O)NR^(a)(CR^(d)R^(d1))_(r)-M,NR^(a)C(O)O(CR^(d)R^(d1))_(r)-M, NR^(a)C(O)NR^(a1)(CR^(d)R^(d1))_(r)-M,S(O)_(p)(CR^(d)R^(d1))_(r)-M, S(O)₂NR^(a)(CR^(d)R^(d1))_(r)-M,NR^(a)S(O)₂(CR^(d)R^(d1))_(r)-M, C(═NCN)NR^(a1)R^(a2);C(═C(H)(NO₂))NR^(a1)R^(a2); a C₃₋₁₀ carbocycle substituted with 0-5R^(d), and a 5-10 membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from the group consisting of N, O, S(O)_(p) andsaid heterocycle being substituted with 0-5 R^(d);

alternatively, two R, together with a carbon atom on A, form the groupC_(A)═CR^(d)R^(d1), where the atom C_(A) is said atom on A;

M is selected from the group consisting of H, C₂₋₁₀ alkenylenesubstituted with 0-3 R^(b1),

C₂₋₁₀ alkynylene substituted with 0-3 R^(b1), OR^(a), Cl, F, Br, —CN,NO₂, NR^(a)R^(a1), C(O)R^(a), C(O)OR^(a), C(O)NR^(a)R^(a1),R^(a)NC(O)NR^(a)R^(a1), OC(O)NR^(a)R^(a1), NR^(a)C(O)OR^(a),NR^(a)C(O)R^(a), S(O)₂NR^(a)R^(a1), NR^(a)S(O)₂R^(a2), S(O)_(p)R^(a2),CF₃, CF₂CF₃, CH₂F, CHF₂, CF₂CH₃, C(CH₃)₂F, OCF₃, OCHF₂, a C₃₋₁₀carbocycle substituted with 0-5 R^(d), and a 5-10 membered heterocyclecomprising carbon atoms and 1-4 heteroatoms selected from the groupconsisting of N, O, S(O)_(p) and said heterocycle being substituted with0-5 R^(d);

alternatively, R, at each occurrence, is independently selected fromC₁₋₁₀ alkylene-M¹,

C₂₋₁₀ alkenylene-M¹, C₂₋₁₀ alkynylene-M¹,(CR^(d)R^(d1))_(r)O(CR^(d)R^(d1))_(r)-M¹,

(CR^(d)R^(d1))_(r)NR^(a)(CR^(d)R^(d1))_(r)-M¹,(CR^(d)R^(d1))_(r)C(O)(CR^(d)R^(d1))_(r)-M¹,

(CR^(d)R^(d1))_(r)C(O)O(CR^(d)R^(d1))_(r)M¹,(CR^(d)R^(d1))_(r)OC(O)(CR^(d)R^(d1))_(r)-M¹,(CR^(d)R^(d1))_(r)C(O)NR^(a)(CR^(d)R^(d1))_(r)-M¹, (CR^(d)R^(d1))_(r)M¹,

(CR^(d)R^(d1))_(r)OC(O)(CR^(d)R^(d1))_(r)-M¹,(CR^(d)R^(d1))_(r)OC(O)NR^(a)(CR^(d)R^(d1))_(r)-M¹,(CR^(d)R^(d1))_(r)NR^(a)C(O)O(CR^(d)R^(d1))_(r)-M¹,(CR^(d)R^(d1))_(r)NR^(a)C(O)NR^(a1)(CR^(d)R^(d1))_(r)-M¹,(CR^(d)R^(d1))_(r)S(O)_(p)(CR^(d)R^(d1))_(r)-M¹,(CR^(d)R^(d1))_(r)S(O)₂NR^(a)(CR^(d)R^(d1))_(r)-M¹, and(CR^(d)R^(d1))_(r)NR^(a)S(O)₂(CR^(d)R^(d1))_(r)-M¹;

M¹ is selected from the group consisting of OR^(a), Cl, F, Br, —CN, NO₂,NR^(a)R^(a1), C(O)R^(a), C(O)OR^(a), C(O)NR^(a)R^(a1),R^(a)NC(O)NR^(a)R^(a1), OC(O)NR^(a)R^(a1), R^(a)NC(O)OR^(a),S(O)₂NR^(a)R^(a1), NR^(a)S(O)₂R^(a2), NR^(a)S(O)₂NR^(a)R^(a1),OS(O)₂NR^(a)R^(a1), S(O)_(p)R^(a2), CF₃, CF₂CF₃, CH₂F, CHF₂, CF₂CH₃,C(CH₃)₂F, OCF₃, and a 5-10 membered non-aromatic heterocycle comprisingcarbon atoms and 1-4 heteroatoms selected from the group consisting ofN, O, S(O)_(p) and said heterocycle being substituted with 0-5 R^(d); aC₃-C₁₀ carbocycle, C₅-C₁₀ heterocycle and wherein said C₃-C₁₀ carbocycleand C₅-C₁₀ heterocycle are substituted with 1-3 R^(h), and CF₃, CF₂CF₃,CH₂F, CHF₂, CF₂CH₃, C(CH₃)₂F, OCF₃, OCHF₂, OCF₂CF₃ and OCH₂CF₃;

alternatively, when two R groups are attached to adjacent ring A atoms,together with the atoms to which they are attached they may form a 3-8membered saturated, partially saturated or unsaturated ring comprised ofcarbon atoms and 0-3 heteroatoms selected from the group consisting ofN, NR^(a), O, and S(O)_(p), wherein said ring may be benzene-fusedand/or substituted with R^(d);

alternatively, when two R groups are attached to the same ring A carbon,together with the carbon to which they are attached they may form a 3-8membered saturated, partially saturated or unsaturated spiro-ringcomprised of carbon atoms and 0-3 heteroatoms selected from the groupconsisting of N, NR^(a), O, and S(O)_(p), wherein said spiro-ring may bebenzene-fused and/or substituted with R^(d);

provided that either two R or M, M¹ and the atom to which they areattached do not combine to form a N—N, N—O, O—N, O—O, N-halogen,O-halogen, S-halogen, S(O)_(p)—O, O—S(O)_(p), S(O)_(p)—S(O)_(p) group,or C(O)F, C(O)Cl, C(O)Br, or C(O)I reactive group;

R^(a), R^(a1), and R^(a2) at each occurrence are independently selectedfrom the group consisting of H, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈alkynyl, wherein said alkyl, alkenyl and alkynyl groups are optionallysubstituted with O (primary, secondary, or tertiary)C₁-C₈, OH, Cl, F,—CN, alkylamino, dialkylamino, alkarylamino, arylamino, alkylcarbonyl,aralkylcarbonyl, arylcarbonyl, carboxyl, alkylcarboxylate, alkylamido,dialkylamido, alkylureidoalkyl, alkylureidodialkyl, carbamoylalkyl,carbamoyldialkyl, alkylcarbamoyl, sulfonamidoalkyl, sulfonamidodialkyl,N-alkylsulfonamidoalkyl, N-alkylsulfonamidoalkyl,N-alkylsufonamidodialkyl, alkylamidosulfonate, dialkylamidosulfonate,alkylsulfinyl, alkylsulfonyl, CF₃, CF₂CF₃, CH₂F, CHF₂, CF₂CH₃, C(CH₃)₂F,OCF₃, and OCH₂CF₃; C₃-C₁₀ carbocycle, heterocycles, C₃-C₁₀carbocyclylalkyl, heterocyclylalkyl and wherein said C₃-C₁₀ carbocycle,heterocycles, C₃-C₁₀ carbocyclylalkyl, and heterocyclylalkyl may beoptionally substituted with one or more substituents selected from thegroup consisting of C₁-C₈ alkyl, O (primary, secondary, ortertiary)C₁-C₈, OH, Cl, F, Br, ═O, —CN, NO₂, alkylamino, dialkylamino,alkarylamino, arylamino, alkylcarbonyl, aralkylcarbonyl, arylcarbonyl,carboxyl, alkylcarboxylate, alkylamido, dialkylamido, alkylureidoalkyl,alkylureidodialkyl, carbamoylalkyl, carbamoyldialkyl, alkylcarbamoyl,sulfonamidoalkyl, sulfonamidodialkyl, N-alkylsulfonamidoalkyl,N-alkylsulfonamido-alkyl, N-alkylsufonamidodialkyl, alkylamidosulfonate,dialkylamidosulfonate, alkylsulfinyl, alkylsulfonyl, CF₃, CH₂F, CHF₂,CF₂CH₃, C(CH₃)₂F, OCF₃, and OCH₂CF₃;

alternatively, R^(a) and R^(a1) taken together with the nitrogen towhich they are attached form a 3 to 8 membered ring containing from 0-1additional heteroatoms selected from the group consisting of N, O, andS, wherein said ring may be substituted with R^(d);

R^(b) at each occurrence is independently selected from the groupconsisting of C₁₋₆ alkyl optionally substituted with R^(c1), O (primary,secondary, or tertiary)C₁-C₈, OH, Cl, F, —CN, NO₂, NR^(a)R^(a1),C(O)R^(a), C(O)OR^(a), C(O)NR^(a)R^(a1), R^(a)NC(O)NR^(a)R^(a),OC(O)NR^(a)R^(a1), R^(a)NC(O)OR^(a1), S(O)₂NR^(a)R^(a1),NR^(a)S(O)₂R^(a2), NR^(a)S(O)₂NR^(a)R^(a1), OS(O)₂NR^(a)R^(a1),

S(O)_(p)R^(a2), CF₃, CH₂F, CHF₂, CF₂CH₃, C(CH₃)₂F, OCF₃, OCHF₂, andOCH₂CF₃; C₃₋₁₀ carbocyclic residue, and a 5-10 membered heterocyclicsystem containing from 1-4 heteroatoms selected from the groupconsisting of N, O, and S, C₃-C₁₀ carbocyclyl(C₁₋₈)alkyl, and 5-10heterocyclyl-(C₁₋₈)alkyl and said C₃₋₁₀ carbocyclic residue,heterocyclic system,

C₃-C₁₀ carbocyclyl(C₁₋₈)alkyl, and 5-10 heterocyclyl(C₁₋₈)alkyl areoptionally substituted with R^(c1);

R^(b1) at each occurrence is independently selected from the groupconsisting of OR^(a), F, ═O, —CN, NO₂, NR^(a)R^(a1) and S(O)_(p)R^(a);

R^(c) at each occurrence is independently selected from the groupconsisting of C₁₋₆ alkyl optionally substituted with R^(c1), OR^(a), Cl,F, —CN, NO₂, NR^(a)R^(a1), C(O)R^(a), C(O)OR^(a), C(O)NR^(a)R^(a1),R^(a)NC(O)NR^(a)R^(a), OC(O)NR^(a)R^(a1), R^(a)NC(O)OR^(a1),S(O)₂NR^(a)R^(a1), NR^(a)S(O)₂R^(a2),

NR^(a)S(O)₂NR^(a)R^(a1), S(O)_(p)R^(a2), CF₃, CH₂F, CHF₂, CF₂CH₃,C(CH₃)₂F, OCF₃, OCHF₂, and OCH₂CF₃; a C₃₋₁₀ carbocyclic residue, and a5-10 membered heterocyclic system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S, C₃-C₁₀carbocyclyl(C₁₋₈)alkyl, and 5-10 heterocyclyl(C₁₋₈)alkyl; said C₃₋₁₀carbocyclic residue, heterocyclic system, C₃-C₁₀ carbocyclyl(C₁₋₈)alkyl,and 5-14 heterocyclyl(C₁₋₈)alkyl are optionally substituted with R.

R^(c1) at each occurrence is independently selected from the groupconsisting of C₁₋₆ alkyl, OR^(a), Cl, F, Br, ═O, —CN, NO₂, NR^(a)R^(a1),C(O)R^(a), C(O)OR^(a), C(O)NR^(a)R^(a1), OC(O)NR^(a)R^(a1),R^(a)NC(O)OR^(a), S(O)₂NR^(a)R^(a1), NR^(a)S(O)₂R^(a2), S(O)_(p)R^(a2),CF₃, and CH₂F, and CHF₂;

R^(d) at each occurrence is independently selected from the groupconsisting of H, C₁₋₆ alkyl optionally substituted with R^(c1), OR^(a),Cl, F, Br, ═O, —CN, NO₂, NR^(a)R^(a1), C(O)R^(a), C(O)OR^(a),C(O)NR^(a)R^(a1), R^(a)NC(O)NR^(a)R^(a), OC(O)NR^(a)R^(a1),R^(a)NC(O)OR^(a1), S(O)₂NR^(a)R^(a1), NR^(a)S(O)₂R^(a2),OS(O)₂NR^(a)R^(a1), S(O)_(p)R^(a2), CF₃, CF₂CF₃, CH₂F, CHF₂, CF₂CH₃,C(CH₃)₂F, OCF₃, OCHF₂, and OCH₂CF₃; C₃₋₁₀ carbocyclic residue, and a5-10 membered heterocyclic system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S, C₃-C₁₀carbocyclyl(C₁₋₈)alkyl, and 5-14 heterocyclyl(C₁₋₈)alkyl; said C₃₋₁₀carbocyclic residue, heterocyclic system C₃-C₁₀ carbocyclyl(C₁₋₈)alkyl,and 5-10 heterocyclyl(C₁₋₈)alkyl optionally substituted with R.

R^(d1) at each occurrence is independently selected from the groupconsisting of H, C₁₋₆ alkyl optionally substituted with R^(c1), OR^(a),Cl, F, —CN, NR^(a)R^(a1), C(O)R^(a), C(O)OR^(a), C(O)NR^(a)R^(a1),R^(a)NC(O)NR^(a)R^(a), OC(O)NR^(a)R^(a1), R^(a)NC(O)OR^(a1),S(O)₂NR^(a)R^(a1), NR^(a)S(O)₂R^(a2), S(O) p R^(a2), CF₃, CH₂F, CHF₂,CF₂CH₃, C(CH₃)₂F, OCF₃, OCHF₂, and OCH₂CF₃; C₃₋₁₀ carbocyclic residue,and a 5-10 membered heterocyclic system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S, C₃-C₁₀carbocyclyl(C₁₋₈)alkyl, and 5-10 heterocyclyl(C₁₋₈)alkyl; said C₃₋₁₀carbocyclic residue, heterocyclic system C₃-C₁₀ carbocyclyl(C₁₋₈)alkyl,and 5-14 heterocyclyl(C₁₋₈)alkyl optionally substituted with R^(c1).

alternatively, R^(d) and R^(d1) taken together with the atom to whichthey are attached form a 4 to 8 membered ring containing from 0-1heteroatoms selected from the group consisting of N, O, and S, whereinsaid ring may be substituted with R^(d);

R^(h) at each occurrence is independently selected from the groupconsisting of OR, NR^(j)R^(a), COR^(j), C(O)OR^(j), C(O)NR^(j)R^(a),NR^(a)C(O)NR^(j)R^(a1), OC(O)NR^(j)R^(a), S(O)_(p)NR^(j)R^(a1),NR^(a)S(O)pR^(j), C₁₋₆ alkyl substituted with R^(c).

R^(j) at each occurrence is independently selected from the groupconsisting of CF₃, CH₂F, CF₂H, CF₂CF₃, C₁-C₈ alkyl substituted with O(primary, secondary, or tertiary)C₁-C₈, OH, Cl, F, —CN, alkylamino,dialkylamino, alkarylamino, arylamino, carboxyl, alkylcarboxylate,alkylamido, dialkylamido, alkylureidoalkyl, alkylureidodialkyl,carbamoylalkyl, carbamoyldialkyl, alkylcarbamoyl, sulfonamidoalkyl,sulfonamidodialkyl, N-alkylsulfonamidoalkyl, N-alkylsulfonamidoalkyl,N-alkylsufonamidodialkyl, alkylamidosulfonate, dialkylamidosulfonate,alkylsulfonyl, CF₃, CH₂F, CHF₂, CF₂CH₃, C(CH₃)₂F, OCF₃, OCHF₂, andOCH₂CF₃; C₂-C₈ alkenyl, C₂-C₈ alkynyl, wherein said alkenyl and alkynylgroups are optionally substituted with C₁-C₈ alkyl, O (primary,secondary, or tertiary)C₁-C₈, OH, Cl, F, —CN, alkylamino, dialkylamino,alkarylamino, arylamino, carboxyl, alkylcarboxylate, alkylamido,dialkylamido, alkylureidoalkyl, alkylureidodialkyl, carbamoylalkyl,carbamoyldialkyl, alkylcarbamoyl, sulfonamidoalkyl, sulfonamidodialkyl,N-alkylsulfonamidoalkyl, N-alkylsulfonamidoalkyl,N-alkylsufonamidodialkyl, alkylamidosulfonate, dialkylamidosulfonate,CF₃, CH₂F, CHF₂, CF₂CH₃, C(CH₃)₂F, OCF₃, OCHF₂, and OCH₂CF₃; C₃-C₁₀carbocycle, 5-10 membered heterocycles, C₃-C₁₀ carbocyclylalkyl,heterocyclylalkyl and wherein said C₃-C₁₀ carbocycle, heterocycles,C₃-C₁₀ carbocyclylalkyl, and heterocyclylalkyl may be optionallysubstituted with one or more substituents selected from the groupconsisting of O (primary, secondary, or tertiary)C₁-C₈, OH, Cl, F, —CN,NO₂, alkylamino, dialkylamino, alkarylamino, arylamino, carboxyl,alkylcarboxylate, alkylamido, dialkylamido, alkylureidoalkyl,alkylureidodialkyl, carbamoylalkyl, carbamoyldialkyl, alkylcarbamoyl,sulfonamidoalkyl, sulfonamidodialkyl, N-alkylsulfonamidoalkyl,N-alkylsulfonamido-alkyl, N-alkylsufonamidodialkyl, alkylamidosulfonate,dialkylamidosulfonate, alkylsulfonyl, CF₃, CH₂F, CHF₂, CF₂CH₃, C(CH₃)₂F,OCF₃, and OCH₂CF₃, with the proviso that said C₃-C₁₀ carbocycle can notbe a phenyl group and C₃-C₁₀ carbocyclylalkyl can not be a benzyl group;

R⁵ at each occurrence is selected from the group consisting of C₁₋₁₀alkyl substituted with 0-2 R^(b), and C₁₋₈ alkyl substituted with 0-2R^(e);

R^(e) at each occurrence is selected from the group consisting of phenylsubstituted with 0-2 R^(b) and biphenyl substituted with 0-2 R^(b);

p at each occurrence is 0, 1, and 2; and

r at each occurrence is 0, or an integer from 1 to 10.

In an even more preferred embodiment, the present invention providespotent matrix metalloprotease inhibitors which are cyclic hydroxamatederivatives according to the formula IIIA or IVA:

wherein ring A is a 5-7 membered non-aromatic carbocycle or heterocyclecomprising carbon atoms, 0-1 carbonyl groups and from 0-2 ringheteroatoms selected from the group consisting of O, N, NR, providedthat ring A contains other than a O—O bond;

n′ is 1 or 2;

P is D-E-G-Q-L-T-X-Y, wherein

D is absent or is selected from the group consisting of O, NR^(a1),C(O), C(O)NR^(a1), NR^(a1)C(O), OC(O)NR^(a1), NR^(a1)C(O)O,NR^(a1)C(O)NR^(a1), S(O)_(p), S(O)_(p)NR^(a1), and NR^(a1)S(O)_(p);

E is absent or is selected from the group consisting of C₁₋₁₀alkylene,C₂₋₁₀ alkenylene, and

C₂₋₁₀ alkynylene;

G is absent or is selected from the group consisting of O, NR^(a1),S(O)_(p), and C(O);

Q is absent or is selected from the group consisting of a C₅₋₇carbocycle substituted with 0-5 R^(b), and a 5-7 membered heterocyclecomprising carbon atoms and 1-4 heteroatoms selected from the groupconsisting of N, O, and S(O)_(p), and said heterocycle being substitutedwith 0-5 R^(b);

L is absent or is selected from the group consisting of O, NR^(a1),C(O), C(O)NR^(a1), NR^(a1)C(O), OC(O)NR^(a1), NR^(a1)C(O)O, S(O)_(p),S(O)_(p)NR^(a1), and NR^(a1)S(O)_(p);

T is absent or is selected from the group consisting of C₁₋₁₀ alkylene,C₂₋₁₀ alkenylene, and C₂₋₁₀ alkynylene;

X is absent or is selected from the group consisting of O, NR^(a1),S(O)_(p), and C(O);

Y is selected from the group consisting of H, a C₅₋₇ carbocyclesubstituted with 0-5 R^(c) and a 5-6 membered heterocycle comprisingcarbon atoms and 1-4 heteroatoms selected from the group consisting ofN, O, and S(O)_(p), and said heterocycle being substituted with 0-5R^(c);

provided that D, E, G, Q, L, T, X and Y do not combine to form a N—N,N—O, O—N, O—O, S(O)_(p)—O, O—S(O)_(p) or S(O)_(p)—S(O)_(p) group;

R, at each occurrence, is independently selected from (C₁₋₁₀ alkylenesubstituted with

1-3 R^(b1))-M, (C₂₋₁₀ alkenylene substituted with 1-3 R^(b1))-M, (C₂₋₁₀alkynylene substituted with 1-3 R^(b1))-M, OH, F, Cl, —CN, NO₂, CF₃,CH₂F, CHF₂, CF₂CH₃, C(CH₃)₂F, OCF₃, OCHF₂, O(CR^(d)R^(d1))_(r)-M¹,NR^(a)(CR^(d)R^(d1))_(r)-M, OC(O)(CR^(d)R^(d1))_(r)-M,NR^(a)C(O)(CR^(d)R^(d1))_(r)-M, OC(O)O(CR^(d)R^(d1))_(r)-M,OC(O)NR^(a)(CR^(d)R^(d1))_(r)-M, NR^(a)C(O)O(CR^(d)R^(d1))_(r)-M,NR^(a)C(O)NR^(a1)(CR^(d)R^(d1))_(r)M, S(O)_(p)(CR^(d)R^(d1))_(r)-M,S(O)₂NR^(a)(CR^(d)R^(d1))_(r)-M, NR^(a)S(O)₂(CR^(d)R^(d1))_(r)-M,C(═NCN)NR^(a1)R^(a2); C(═C(H)(NO₂))NR^(a1)R^(a2); a C₃₋₁₀ carbocyclesubstituted with 0-5 R^(d), and a 5-10 membered heterocycle comprisingcarbon atoms and 1-4 heteroatoms selected from the group consisting ofN, O, S(O)_(p) and said heterocycle being substituted with 0-5 R^(d);

-   -   alternatively, two R, together with a carbon atom on A, form the        group C_(A)═CR^(d)R^(d1), where the atom C_(A) is said atom on        A;

M is selected from the group consisting of H, C₂₋₁₀ alkenylenesubstituted with 0-3 R^(b1),

C₂₋₁₀ alkynylene substituted with 0-3 R^(b1), OR^(a), Cl, F, —CN, NO₂,NR^(a)R^(a1), C(O)R^(a), C(O)OR^(a), C(O)NR^(a)R^(a1),R^(a)NC(O)NR^(a)R^(a1), OC(O)NR^(a)R^(a1), NR^(a)C(O)OR^(a),NR^(a)C(O)R^(a), S(O)₂NR^(a)R^(a1), NR^(a)S(O)₂R^(a2), S(O)_(p)R^(a2),CF₃, CH₂F, CHF₂, CF₂CH₃, C(CH₃)₂F, OCF₃, OCHF₂, a C₃₋₁₀ carbocyclesubstituted with 0-5 R^(d), and a 5-10 membered heterocycle comprisingcarbon atoms and 1-4 heteroatoms selected from the group consisting ofN, O, S(O)_(p) and said heterocycle being substituted with 0-5 R^(d);

alternatively, R, at each occurrence, is independently selected fromC₁₋₁₀ alkylene-M¹, C₂₋₁₀ alkenylene-M¹, C₂₋₁₀ alkynylene-M¹,(CR^(d)R^(d1))_(r)O(CR^(d)R^(d1))_(r)-M¹,

(CR^(d)R^(d1))_(r)NR^(a)(CR^(d)R^(d1))_(r)-M¹, (CR^(d)R^(d1))_(r)C(O)(CR^(d)R^(d1))_(r)-M¹,

(CR^(d)R^(d1))_(r)C(O)O(CR^(d)R^(d1))_(r)-M¹,(CR^(d)R^(d1))_(r)OC(O)(CR^(d)R^(d1))_(r)-M¹,(CR^(d)R^(d1))_(r)C(O)NR^(a)(CR^(d)R^(d1))_(r)-M¹,(CR^(d)R^(d1))_(r)NR^(a)C(O)(CR^(d)R^(d1))_(r)-M¹,

(CR^(d)R^(d1))_(r)OC(O)O(CR^(d)R^(d1))_(r)-M¹,(CR^(d)R^(d1))_(r)OC(O)NR^(a)(CR^(d)R^(d1))_(r)-M¹,(CR^(d)R^(d1))_(r)NR^(a)C(O)O(CR^(d)R^(d1))_(r)-M¹,(CR^(d)R^(d1))_(r)NR^(a)C(O)NR^(a1)(CR^(d)R^(d1))_(r)-M¹,(CR^(d)R^(d1))_(r)S(O)_(p)(CR^(d)R^(d1))_(r)-M¹,(CR^(d)R^(d1))_(r)S(O)₂NR^(a)(CR^(d)R^(d1))_(r)-M¹, and(CR^(d)R^(d1))_(r)NR^(a)S(O)₂(CR^(d)R^(d1))_(r)-M¹;

M¹ is selected from the group consisting of OR^(a), Cl, F, Br, —CN, NO₂,NR^(a)R^(a1), C(O)R^(a), C(O)OR^(a), C(O)NR^(a)R^(a1),R^(a)NC(O)NR^(a)R^(a1), OC(O)NR^(a)R^(a1), R^(a)NC(O)OR^(a),S(O)₂NR^(a)R^(a1), NR^(a)S(O)₂R^(a2), OS(O)₂NR^(a)R^(a1),S(O)_(p)R^(a2), CF₃, CF₂CF₃, CH₂F, CHF₂, CF₂CH₃, C(CH₃)₂F, OCF₃, and a5-10 membered non-aromatic heterocycle comprising carbon atoms and 1-4heteroatoms selected from the group consisting of N, O, S(O)_(p) andsaid heterocycle being substituted with 0-5 R^(d); a C₃-C₁₀ carbocycle,C₅-C₁₀ heterocycle and wherein said C₃-C₁₀ carbocycle and C₅-C₁₀heterocycle are substituted with 1-3 R^(h), and CF₃, CF₂CF₃, CH₂F, CHF₂,CF₂CH₃, C(CH₃)₂F, OCF₃, OCHF₂, OCF₂CF₃ and OCH₂CF₃;

provided that either two R or M, M¹ and the atom to which they areattached do not combine to form a N—N, N—O, O—N, O—O, N-halogen,O-halogen, S-halogen, S(O)_(p)—O, O—S(O)_(p), S(O)_(p)—S(O)_(p) group,or C(O)F, C(O)Cl, C(O)Br, or C(O)I reactive group;

R^(a), R^(a1), and R^(a2) at each occurrence are independently selectedfrom the group consisting of H, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈alkynyl; C₃-C₁₀ carbocycle, heterocycles, C₃-C₁₀ carbocyclylalkyl,heterocyclylalkyl;

alternatively, R^(a) and R^(a1) taken together with the nitrogen towhich they are attached form a 3 to 8 membered ring containing from 0-1additional heteroatoms selected from the group consisting of N, O, andS, wherein said ring may be substituted with R^(d);

R^(b) at each occurrence is independently selected from the groupconsisting of C₁₋₆ alkyl optionally substituted with R^(c1), O (primary,secondary, or tertiary)C₁-C₈, OH, Cl, F, —CN, NO₂, NR^(a)R^(a1),C(O)R^(a), C(O)OR^(a), C(O)NR^(a)R^(a1), R^(a)NC(O)NR^(a)R^(a),OC(O)NR^(a)R^(a1), R^(a)NC(O)OR^(a1), S(O)₂NR^(a)R^(a1),NR^(a)S(O)₂R^(a2), NR^(a)S(O)₂NR^(a)R^(a1), OS(O)₂NR^(a)R^(a1),S(O)_(p)R^(a2), CF₃, CH₂F, CHF₂, CF₂CH₃, C(CH₃)₂F, OCF₃, OCHF₂, andOCH₂CF₃; C₃₋₁₀ carbocyclic residue, and a 5-10 membered heterocyclicsystem containing from 1-4 heteroatoms selected from the groupconsisting of N, O, and S, C₃-C₁₀ carbocyclyl(C₁₋₈)alkyl, and 5-10heterocyclyl-(C₁₋₈)alkyl and said C₃₋₁₀ carbocyclic residue,heterocyclic system,

C₃-C₁₀ carbocyclyl(C₁₋₈)alkyl, and 5-10 heterocyclyl(C₁₋₈)alkyl areoptionally substituted with R^(c1);

R^(b1) at each occurrence is independently selected from the groupconsisting of OR^(a), F, —CN, NR^(a)R^(a1) and S(O)_(p)R^(a);

R^(c) at each occurrence is independently selected from the groupconsisting of C₁₋₆ alkyl optionally substituted with R^(c1), OR^(a), Cl,F, —CN, NO₂, NR^(a)R^(a1), C(O)R^(a), C(O)OR^(a), C(O)NR^(a)R^(a1),R^(a)NC(O)NR^(a)R^(a), OC(O)NR^(a)R^(a1), R^(a)NC(O)OR^(a1),S(O)₂NR^(a)R^(a1), NR^(a)S(O)₂R^(a2),

NR^(a)S(O)₂NR^(a)R^(a1), S(O)_(p)R^(a2), CF₃, CH₂F, CHF₂, CF₂CH₃,C(CH₃)₂F, OCF₃, OCHF₂, and OCH₂CF₃; a C₃₋₁₀ carbocyclic residue, and a5-10 membered heterocyclic system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S, C₃-C₁₀carbocyclyl(C₁₋₈)alkyl, and 5-10 heterocyclyl(C₁₋₈)alkyl; said C₃₋₁₀carbocyclic residue, heterocyclic system, C₃-C₁₀ carbocyclyl(C₁₋₈)alkyl,and 5-14 heterocyclyl(C₁₋₈)alkyl are optionally substituted with R^(c1);

R^(c1) at each occurrence is independently selected from the groupconsisting of C₁₋₆ alkyl, OR^(a), Cl, F, —CN, NO₂, NR^(a)R^(a1),C(O)R^(a), C(O)OR^(a), C(O)NR^(a)R^(a1), OC(O)NR^(a)R^(a1),R^(a)NC(O)OR^(a), S(O)₂NR^(a)R^(a1), NR^(a)S(O)₂R^(a2), S(O)_(p)R^(a2),CF₃, and CH₂F, and CHF₂;

R^(d) at each occurrence is independently selected from the groupconsisting of H, C₁₋₆ alkyl optionally substituted with R^(c1), OR^(a),Cl, F, —CN, NO₂, NR^(a)R^(a1), C(O)R^(a), C(O)OR^(a), C(O)NR^(a)R^(a1),R^(a)NC(O)NR^(a)R^(a), OC(O)NR^(a)R^(a1), R^(a)NC(O)OR^(a1),S(O)₂NR^(a)R^(a1), NR^(a)S(O)₂R^(a2), S(O)_(p)R^(a2), CF₃, CH₂F, CHF₂,CF₂CH₃, C(CH₃)₂F, OCF₃, OCHF₂, and OCH₂CF₃; C₃₋₁₀ carbocyclic residue,and a 5-10 membered heterocyclic system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S, C₃-C₁₀carbocyclyl(C₁₋₈)alkyl, and 5-14 heterocyclyl(C₁₋₈)alkyl; said C₃₋₁₀carbocyclic residue, heterocyclic system C₃-C₁₀ carbocyclyl(C₁₋₈)alkyl,and 5-10 heterocyclyl(C₁₋₈)alkyl optionally substituted with R^(c1).

R^(d1) at each occurrence is independently selected from the groupconsisting of H, C₁₋₆ alkyl optionally substituted with R^(c1), OR^(a),Cl, F, —CN, NR^(a)R^(a1), C(O)R^(a), C(O)OR^(a), C(O)NR^(a)R^(a1),R^(a)NC(O)NR^(a)R^(a), OC(O)NR^(a)R^(a1), R^(a) NC(O)OR^(a1),S(O)₂NR^(a)R^(a1), NR^(a)S(O)₂R^(a2), S(O)_(p)R^(a2), CF₃, CH₂F, CHF₂,CF₂CH₃, C(CH₃)₂F, OCF₃, OCHF₂, and OCH₂CF₃; C₃₋₁₀ carbocyclic residue,and a 5-10 membered heterocyclic system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S, C₃-C₁₀carbocyclyl(C₁₋₈)alkyl, and 5-10 heterocyclyl(C₁₋₈)alkyl; said C₃₋₁₀carbocyclic residue, heterocyclic system C₃-C₁₀ carbocyclyl(C₁₋₈)alkyl,and 5-14 heterocyclyl(C₁₋₈)alkyl optionally substituted with R^(c1).

alternatively, R^(d) and R^(d1) taken together with the atom to whichthey are attached form a 4 to 8 membered ring containing from 0-1heteroatoms selected from the group consisting of N, O, and S, whereinsaid ring may be substituted with R^(d);

R^(h) at each occurrence is independently selected from the groupconsisting of OR^(j), NR^(j)R^(a), COR^(j), C(O)OR^(j), C(O)NR^(j)R^(a),NR^(a)C(O)NR^(j)R^(a1), OC(O)NR^(j)R^(a), S(O)_(p)NR^(j)R^(a1),NR^(a)S(O)pR^(j), C₁₋₆ alkyl substituted with R^(c).

R^(j) at each occurrence is independently selected from the groupconsisting of CF₃, CF₂H, CFH₂, CF₂CF₃, C₁-C₈ alkyl substituted with O(primary, secondary, or tertiary)C₁-C₈, OH, Cl, F, —CN, alkylamino,dialkylamino, alkarylamino, arylamino, carboxyl, alkylcarboxylate,alkylamido, dialkylamido, alkylureidoalkyl, alkylureidodialkyl,carbamoylalkyl, carbamoyldialkyl, alkylcarbamoyl, sulfonamidoalkyl,sulfonamidodialkyl, N-alkylsulfonamidoalkyl, N-alkylsulfonamidoalkyl,N-alkylsufonamidodialkyl, alkylamidosulfonate, dialkylamidosulfonate,alkylsulfonyl, CF₃, CH₂F, CHF₂, CF₂CH₃, C(CH₃)₂F, OCF₃, OCHF₂, andOCH₂CF₃; C₂-C₈ alkenyl, C₂-C₈ alkynyl, wherein said alkenyl and alkynylgroups are optionally substituted with C₁-C₈ alkyl, O (primary,secondary, or tertiary)C₁-C₈, OH, Cl, F, —CN, alkylamino, dialkylamino,alkarylamino, arylamino, carboxyl, alkylcarboxylate, alkylamido,dialkylamido, alkylureidoalkyl, alkylureidodialkyl, carbamoylalkyl,carbamoyldialkyl, alkylcarbamoyl, sulfonamidoalkyl, sulfonamidodialkyl,N-alkylsulfonamidoalkyl, N-alkylsulfonamidoalkyl,N-alkylsufonamidodialkyl, alkylamidosulfonate, dialkylamidosulfonate,CF₃, CH₂F, CHF₂, CF₂CH₃, C(CH₃)₂F, OCF₃, OCHF₂, and OCH₂CF₃; C₃-C₁₀carbocycle, 5-10 membered heterocycles, C₃-C₁₀ carbocyclylalkyl,heterocyclylalkyl and wherein said C₃-C₁₀ carbocycle, heterocycles,C₃-C₁₀ carbocyclylalkyl, and heterocyclylalkyl may be optionallysubstituted with one or more substituents selected from the groupconsisting of O (primary, secondary, or tertiary)C₁-C₈, OH, Cl, F, —CN,NO₂, alkylamino, dialkylamino, alkarylamino, arylamino, carboxyl,alkylcarboxylate, alkylamido, dialkylamido, alkylureidoalkyl,alkylureidodialkyl, carbamoylalkyl, carbamoyldialkyl, alkylcarbamoyl,sulfonamidoalkyl, sulfonamidodialkyl, N-alkylsulfonamidoalkyl,N-alkylsulfonamido-alkyl, N-alkylsufonamidodialkyl, alkylamidosulfonate,dialkylamidosulfonate, alkylsulfonyl, CF₃, CH₂F, CHF₂, CF₂CH₃, C(CH₃)₂F,OCF₃, and OCH₂CF₃, with the proviso that said C₃-C₁₀ carbocycle can notbe a phenyl group and C₃-C₁₀ carbocyclylalkyl can not be a benzyl group;

p at each occurrence is 0, 1, and 2; and

r at each occurrence is 0, or an integer from 1 to 10.

In a particular preferred embodiment, the compound is of the formula VAor VIA as shown below

wherein J, K and W are independently selected from the group consistingof —(CH₂)_(n)—, NH, NR, O, n=1-3, and n′=1 or 2, with the proviso that Jand K, and K and W can not be N—N, N—O or O—O;

P is -D-Q-L-Y, wherein

D is absent or is selected from the group consisting of C(O),C(O)NR^(a1), NR^(a1)C(O), S(O)_(p), S(O)_(p)NR^(a1), andNR^(a1)S(O)_(p);

Q is absent or is selected from the group consisting of a C₅₋₇carbocycle substituted with 0-5 R^(b), and a 5-7 membered heterocyclecomprising carbon atoms and 1-4 heteroatoms selected from the groupconsisting of N, O, and S(O)_(p), and said heterocycle being substitutedwith 0-5 R^(b);

L is absent or is selected from the group consisting of O;

Y is selected from the group consisting of H, a C₅₋₇ carbocyclesubstituted with 0-5 R^(c) and a 5-6 membered heterocycle comprisingcarbon atoms and 1-4 heteroatoms selected from the group consisting ofN, O, and S(O)_(p), and said heterocycle being substituted with 0-5R^(c);

provided that D, Q, L and Y do not combine to form a N—N, N—O, O—N, O—O,S(O)_(p)—O, O—S(O)_(p) or S(O)_(p)—S(O)_(p) group;

R, at each occurrence, is independently selected from OH, F, Cl, —CN,NO₂, CF₃, CH₂F, CHF₂, CF₂CH₃, C(CH₃)₂F, OCF₃, OCHF₂,O(CR^(d)R^(d1))_(r)-M, NR^(a)(CR^(d)R^(d1))_(r)-MNR^(a)C(O)(CR^(d)R^(d1))_(r)-M, OC(O)O(CR^(d)R^(d1))_(r)-M,OC(O)NR^(a)(CR^(d)R^(d1))_(r)-M, NR^(a)C(O)O(CR^(d)R^(d1))_(r)-M,NR^(a)C(O)NR^(a1)(CR^(d)R^(d1))_(r)-M, S(O)_(p)(CR^(d)R^(d1))_(r)-M,S(O)₂NR^(a)(CR^(d)R^(d1))_(r)-M, NR^(a)S(O)₂(CR^(d)R^(d1))_(r)-M,C(═NCN)NR^(a1)R^(a2); C(═C(H)(NO₂))NR^(a1)R^(a2); a C₃₋₁₀ carbocyclesubstituted with 0-5 R^(d), and a 5-10 membered heterocycle comprisingcarbon atoms and 1-4 heteroatoms selected from the group consisting ofN, O, S(O)_(p) and said heterocycle being substituted with 0-5 R^(d);

alternatively, two R, together with a carbon atom on the ring bearing Jand K or K and W form the group C_(A)═CR^(d)R^(d1), where the atom C_(A)is said atom on the ring bearing J and K or K and W;

M is selected from the group consisting of H, OR^(a), Cl, F, —CN, NO₂,NR^(a)R^(a1), C(O)NR^(a)R^(a1), R^(a)NC(O)NR^(a)R^(a1),OC(O)NR^(a)R^(a1), NR^(a)C(O)OR^(a), NR^(a)C(O)R^(a), S(O)₂NR^(a)R^(a1),NR^(a)S(O)₂R^(a2), S(O)_(p)R^(a2), CF₃, CH₂F, CHF₂, CF₂CH₃, C(CH₃)₂F,OCF₃, OCHF₂, a C₃₋₁₀ carbocycle substituted with 0-5 R^(d), and a 5-10membered heterocycle comprising carbon atoms and 1-4 heteroatomsselected from the group consisting of N, O, S(O)_(p) and saidheterocycle being substituted with 0-5 R^(d);

alternatively, R, at each occurrence, is independently selected C₁₋₁₀alkylene-M¹,

C₂₋₁₀ alkenylene-M¹, C₂₋₁₀ alkynylene-M¹,(CR^(d)R^(d1))_(r)O(CR^(d)R^(d1))_(r)-M¹,

(CR^(d)R^(d1))_(r)NR^(a)(CR^(d)R^(d1))_(r)-M¹,(CR^(d)R^(d1))_(r)C(O)(CR^(d)R^(d1))_(r)-M¹,(CR^(d)R^(d1))_(r)C(O)O(CR^(d)R^(d1))_(r)-M¹,(CR^(d)R^(d1))_(r)C(O)NR^(a)(CR^(d)R^(d1))_(r)-M¹,(CR^(d)R^(d1))_(r)NR^(a)C(O)(CR^(d)R^(d1))_(r)-M¹,

(CR^(d)R^(d1))_(r)OC(O)O(CR^(d)R^(d1))_(r)-M¹,(CR^(d)R^(d1))_(r)OC(O)NR^(a)(CR^(d)R^(d1))_(r)-M¹,(CR^(d)R^(d1))_(r)NR^(a)C(O)O(CR^(d)R^(d1))_(r)-M¹,(CR^(d)R^(d1))_(r)NR^(a)C(O)NR^(a)(CR^(d)R^(d1))_(r)-M¹,(CR^(d)R^(d1))_(r)S(O)_(p)(CR^(d)R^(d1))_(r)-M¹,(CR^(d)R^(d1))_(r)S(O)₂NR^(a)(CR^(d)R^(d1))_(r)-M¹, and(CR^(d)R^(d1))_(r)NR^(a)S(O)₂(CR^(d)R^(d1))_(r)-M¹;

M¹ is selected from the group consisting of OR^(a), Cl, F, Br, —CN, NO₂,NR^(a)R^(a1), C(O)NR^(a)R^(a1), R^(a)NC(O)NR^(a)R^(a1),OC(O)NR^(a)R^(a1), R^(a)NC(O)OR^(a), S(O)₂NR^(a)R^(a1),NR^(a)S(O)₂R^(a2), OS(O)₂NR^(a)R^(a1), S(O)_(p)R^(a2), CF₃, CF₂CF₃,CH₂F, CHF₂, CF₂CH₃, C(CH₃)₂F, OCF₃, and a 5-10 membered non-aromaticheterocycle comprising carbon atoms and 1-4 heteroatoms selected fromthe group consisting of N, O, S(O)_(p) and said heterocycle beingsubstituted with 0-5 R^(d); a C₃-C₁₀ carbocycle, C₅-C₁₀ heterocycle andwherein said C₃-C₁₀ carbocycle and C₅-C₁₀ heterocycle are substitutedwith 1-3 R^(h), and CF₃, CF₂CF₃, CH₂F, CHF₂, CF₂CH₃, C(CH₃)₂F, OCF₃,OCHF₂, OCF₂CF₃ and OCH₂CF₃;

provided that either two R or M, M¹ and the atom to which they areattached do not combine to form a N—N, N—O, O—N, O—O, N-halogen,O-halogen, S-halogen, S(O)_(p)—O, O—S(O)_(p), S(O)_(p)—S(O)_(p) group,or C(O)F, C(O)Cl, C(O)Br, or C(O)I reactive group;

R^(a), R^(a1), and R^(a2) at each occurrence are independently selectedfrom the group consisting of H, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈alkynyl; C₃-C₁₀ carbocycle, heterocycles, C₃-C₁₀ carbocyclylalkyl,heterocyclylalkyl;

alternatively, R^(a) and R^(a1) taken together with the nitrogen towhich they are attached form a 3 to 8 membered ring containing from 0-1additional heteroatoms selected from the group consisting of N, O, andS, wherein said ring may be substituted with R^(d);

R^(b) at each occurrence is independently selected from the groupconsisting of C₁₋₆ alkyl optionally substituted with R^(c1), O (primary,secondary, or tertiary)C₁-C₈, OH, Cl, F, —CN, NO₂, NR^(a)R^(a1),C(O)NR^(a)R^(a1), R^(a) NC(O)NR^(a)R^(a), OC(O)NR^(a)R^(a1),R^(a)NC(O)OR^(a1), S(O)₂NR^(a)R^(a1), NR^(a)S(O)₂R^(a2), S(O)_(p)R^(a2),CF₃, CH₂F, CHF₂, CF₂CH₃, C(CH₃)₂F, OCF₃, OCHF₂, and OCH₂CF₃;

R^(c) at each occurrence is independently selected from the groupconsisting of C₁₋₆ alkyl optionally substituted with R^(c1), OR^(a), Cl,F, —CN, NO₂, NR^(a)R^(a1), C(O)NR^(a)R^(a1), R^(a)NC(O)NR^(a),OC(O)NR^(a)R^(a1), R^(a)NC(O)OR^(a1), S(O)₂NR^(a)R^(a1),NR^(a)S(O)₂R^(a2), S(O)_(p)R^(a2), CF₃, CH₂F, CHF₂, CF₂CH₃, C(CH₃)₂F,OCF₃, OCHF₂, and OCH₂CF₃; a C₃₋₁₀ carbocyclic residue, and a 5-10membered heterocyclic system containing from 1-4 heteroatoms selectedfrom the group consisting of N, O, and S, C₃-C₁₀ carbocyclyl(C₁₋₈)alkyl,and 5-10 heterocyclyl(C₁₋₈)alkyl; said C₃₋₁₀ carbocyclic residue,heterocyclic system, C₃-C₁₀ carbocyclyl(C₁₋₈)alkyl, and 5-14heterocyclyl(C₁₋₈)alkyl are optionally substituted with R^(c1);

R^(c1) at each occurrence is independently selected from the groupconsisting of C₁₋₆ alkyl, OR^(a), Cl, F, —CN, NO₂, NR^(a)R^(a1),C(O)R^(a), C(O)OR^(a), C(O)NR^(a)R^(a1), OC(O)NR^(a)R^(a1),R^(a)NC(O)OR^(a), S(O)₂NR^(a)R^(a1), NR^(a)S(O)₂R^(a2), S(O)_(p)R^(a2),CF₃, and CH₂F, and CHF₂;

R^(d) at each occurrence is independently selected from the groupconsisting of H, C₁₋₆ alkyl optionally substituted with R^(c1), OR^(a),Cl, F, —CN, NO₂, NR^(a)R^(a1), C(O)NR^(a)R^(a1), R^(a) NC(O)NR^(a)R^(a),OC(O)NR^(a)R^(a1), R^(a)NC(O)OR^(a1), S(O)₂NR^(a)R^(a1),NR^(a)S(O)₂R^(a2), S(O)_(p)R^(a1), CF₃, CH₂F, CHF₂, CF₂CH₃, C(CH₃)₂F,OCF₃, OCHF₂, and OCH₂CF₃; C₃₋₁₀ carbocyclic residue, and a 5-10 memberedheterocyclic system containing from 1-4 heteroatoms selected from thegroup consisting of N, O, and S, C₃-C₁₀ carbocyclyl(C₁₋₈)alkyl, and 5-14heterocyclyl(C₁₋₈)alkyl; said C₃₋₁₀ carbocyclic residue, heterocyclicsystem C₃-C₁₀ carbocyclyl(C₁₋₈)alkyl, and 5-10 heterocyclyl(C₁₋₈)alkyloptionally substituted with R^(c1).

R^(d1) at each occurrence is independently selected from the groupconsisting of H, C₁₋₆ alkyl optionally substituted with R^(c1), OR^(a),Cl, F, —CN, NR^(a)R^(a1), C(O)NR^(a)R^(a1), R^(a)NC(O)NR^(a)R^(a),OC(O)NR^(a)R^(a1), R^(a)NC(O)OR^(a1), S(O)₂NR^(a)R^(a1),NR^(a)S(O)₂R^(a1), S(O)_(p)R^(a2), CF₃, CH₂F, CHF₂, CF₂CH₃, C(CH₃)₂F,OCF₃, OCHF₂, and OCH₂CF₃; C₃₋₁₀ carbocyclic residue, and a 5-10 memberedheterocyclic system containing from 1-4 heteroatoms selected from thegroup consisting of N, O, and S, C₃-C₁₀ carbocyclyl(C₁₋₈)alkyl, and 5-10heterocyclyl(C₁₋₈)alkyl; said C₃₋₁₀ carbocyclic residue, heterocyclicsystem C₃-C₁₀ carbocyclyl(C₁₋₈)alkyl, and 5-14 heterocyclyl(C₁₋₈)alkyloptionally substituted with R^(c).

alternatively, R^(d) and R^(d1) taken together with the atom to whichthey are attached form a 4 to 8 membered ring containing from 0-1heteroatoms selected from the group consisting of N, O, and S, whereinsaid ring may be substituted with R^(d);

R^(h) at each occurrence is independently selected from the groupconsisting of OR^(j), NR^(j)R^(a), COR^(j), C(O)OR^(j), C(O)NR^(j)R^(a),NR^(a)C(O)NR^(j)R^(a1), OC(O)NR^(j)R^(a), S(O)_(p)NR^(j)R^(a1),NR^(a)S(O)pR^(j), C₁₋₆ alkyl substituted with R^(c).

R^(j) at each occurrence is independently selected from the groupconsisting of CF₃, CHF₂, CH₂F, CF₂CF₃, C₁-C₈ alkyl substituted with O(primary, secondary, or tertiary)C₁-C₈, OH, Cl, F, —CN, alkylamino,dialkylamino, alkarylamino, arylamino, alkylamido, dialkylamido,carbamoylalkyl, carbamoyldialkyl, alkylcarbamoyl, sulfonamidoalkyl,sulfonamidodialkyl, N-alkylsulfonamidoalkyl, N-alkylsulfonamidoalkyl,N-alkylsufonamidodialkyl, alkylsulfonyl, CF₃, CH₂F, CHF₂, CF₂CH₃,C(CH₃)₂F, OCF₃, OCHF₂, and OCH₂CF₃; C₂-C₈ alkenyl, C₂-C₈ alkynyl,wherein said alkenyl and alkynyl groups are optionally substituted withC₁-C₈ alkyl, O (primary, secondary, or tertiary)C₁-C₈, OH, Cl, F, —CN,alkylamino, dialkylamino, alkarylamino, arylamino, alkylamido,dialkylamido, carbamoylalkyl, carbamoyldialkyl, alkylcarbamoyl,sulfonamidoalkyl, sulfonamidodialkyl, N-alkylsulfonamidoalkyl,N-alkylsulfonamidoalkyl, N-alkylsufonamidodialkyl, CF₃, CH₂F, CHF₂,CF₂CH₃, C(CH₃)₂F, OCF₃, OCHF₂, and OCH₂CF₃; C₃-C₁₀ carbocycle, 5-10membered heterocycles, C₃-C₁₀ carbocyclylalkyl, heterocyclylalkyl andwherein said C₃-C₁₀ carbocycle, heterocycles, C₃-C₁₀ carbocyclylalkyl,and heterocyclylalkyl may be optionally substituted with one or moresubstituents selected from the group consisting of O (primary,secondary, or tertiary)C₁-C₈, OH, Cl, F, —CN, NO₂, alkylamino,dialkylamino, alkarylamino, arylamino, alkylamido, dialkylamido,carbamoylalkyl, carbamoyldialkyl, alkylcarbamoyl, sulfonamidoalkyl,sulfonamidodialkyl, N-alkylsulfonamidoalkyl, N-alkylsulfonamido-alkyl,N-alkylsufonamidodialkyl, alkylsulfonyl, CF₃, CH₂F, CHF₂, CF₂CH₃,C(CH₃)₂F, OCF₃, and OCH₂CF₃, with the proviso that said C₃-C₁₀carbocycle can not be a phenyl group and C₃-C₁₀ carbocyclylalkyl can notbe a benzyl group;

p at each occurrence is 0, 1, and 2; and

r at each occurrence is 0, or an integer from 1 to 10.

Additional embodiments associated with the particularly preferredcompounds of formula III, IIIA, IV, IVA, V, VA, VI, or VIA includepharmaceutical compositions comprised of a compound of formula III,IIIA, IV, IVA, V, VA, VI, or VIA (inclusive of salts, enantiomer,diastereomers, prodrug forms and other derivatives as hereinabovedescribed) in conjunction with at least one pharmaceutically acceptablecarrier, and numerous therapeutic methods accomplished by administeringthese compositions to mammalian subjects in need of metalloproteaseinhibition.

The term “alkyl” when used either alone or as a suffix includes straightchain and branched structures such as primary alkyl groups, secondaryalkyl groups and tertiary alkyl groups. These groups may contain up to15, preferably up to 8 and more preferably up to 4 carbon atoms.Similarly the terms “alkenyl” and “alkynyl” refer to unsaturatedstraight or branched structures containing for example from 2 to 12,preferably from 2 to 6 carbon atoms. Cyclic moieties such as cycloalkyl,cycloalkenyl and cycloalkynyl are similar in nature but have at least 3carbon atoms. Examples of saturated hydrocarbon radicals include groupssuch as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl,sec-butyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, homologsand isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, andthe like. Examples of unsaturated alkyl groups include vinyl,2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl,3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and thehigher homologs and isomers. In the present application, “cycloalkyl” isalso intended to include adamantyl groups and other bridge compounds.The terms “alkoxy”, “alkylamino” and “alkylthio” (or “thioalkoxy”) areused in their conventional sense, and refer to those alkyl groupsattached to the remainder of the molecule via an oxygen atom, an aminogroup, or a sulfur atom, respectively. Therefore, terms such as “alkoxy”and “thioalkyl” comprise alkyl moieties as defined above, attached tothe appropriate functionality.

Other suitable substituents which can be used in the many carbon ringsof the present invention (such as but not limited to cycloaliphatic,aromatic, non-aromatic heterocyclic rings or benzyl group) include, forexample, —OH, halogen (—Br, —Cl, —I and —F) —O (aliphatic, substitutedaliphatic, benzyl, substituted benzyl, aromatic or substituted aromaticgroup), —CN, —NO₂, —COOH, —NH2, —NH (aliphatic group, substitutedaliphatic, benzyl, substituted benzyl, aromatic or substituted aromaticgroup), —N(aliphatic group, substituted aliphatic, benzyl, substitutedbenzyl, aromatic or substituted aromatic group)₂, —COO (aliphatic group,substituted aliphatic, benzyl, substituted benzyl, aromatic orsubstituted aromatic group), —CONH₂, —CONH (aliphatic, substitutedaliphatic group, benzyl, substituted benzyl, aromatic or substitutedaromatic group)), —SH, —S(aliphatic, substituted aliphatic, benzyl,substituted benzyl, aromatic or substituted aromatic group) and—NH—C═NH)—NH2. A substituted non-aromatic heterocyclic ring, benzylicgroup or aromatic group can also have an aliphatic or substitutedaliphatic group as a substituent. A substituted alkyl or aliphatic groupcan also have a non-aromatic heterocyclic ring, benzyl, substitutedbenzyl, aromatic or substituted aromatic group as a substituent. Asubstituted non-aromatic heterocyclic ring can also have ═O, ═S, ═NH or═N (aliphatic, aromatic or substituted aromatic group) as a substituent.A substituted aliphatic, substituted aromatic, substituted non-aromaticheterocyclic ring or substituted benzyl group can have more than onesubstituent.

The terms “halo” or “halogen”, by themselves or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. Similarly, terms such as “haloalkyl”, are meantto include monohaloalkyl and polyhaloalkyl. For example, the term“halo(C₁-C₄)alkyl” is mean to include trifluoromethyl,2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

The term “C₃-C₁₃ carbocyclic group” is intended to include allcycloaliphatic groups selected from the group consisting of cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononylall the way up to a cyclic C₁₃ group. The above cycloaliphatic groupsmay also have unsaturation where appropriate and where there is no highring strain as a result of the double bond. Additionally, the term“C₃-C₁₃ carbocyclic group” is also intended to include bridged and fusedring systems such as adamantyl, [3.3.0]bicyclooctane,[4.3.0]bicyclononane, [4.4.0]bicyclodecane, [2.2.2]bicyclooctane,norbornyl, menthenyl, fluorenyl, phenyl, naphthyl, indanyl, indenyl,anthracenyl and hydrogenated derivatives, phenanthrenyl and hydrogenatedderivatives and tetrahydronaphthyl. The C₃-C₁₃ carbocyclic group asdefined above may also be substituted with —OH, halogen (—Br, —Cl, —Iand —F) —O (aliphatic, substituted aliphatic, benzyl, substitutedbenzyl, aromatic or substituted aromatic group), —CN, —NO₂, —COOH, —NH2,—NH (aliphatic group, substituted aliphatic, benzyl, substituted benzyl,aromatic or substituted aromatic group), —N(aliphatic group, substitutedaliphatic, benzyl, substituted benzyl, aromatic or substituted aromaticgroup)₂, —COO (aliphatic group, substituted aliphatic, benzyl,substituted benzyl, aromatic or substituted aromatic group), —CONH₂,—CONH (aliphatic, substituted aliphatic group, benzyl, substitutedbenzyl, aromatic or substituted aromatic group)), —SH, —S(aliphatic,substituted aliphatic, benzyl, substituted benzyl, aromatic orsubstituted aromatic group) and —N—HC═NH)—NH2.

The terms “3-13 membered heterocyclic system containing from 0-4heteroatoms” and “5-14 membered heterocyclic system containing from 1-4heteroatoms” are intended to include aromatic and non aromaticheterocyclic systems. The 3-13 membered heterocyclic is intended toinclude a 3, 4, 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9,10, 11, 12, or 13 membered bicyclic heterocyclic ring which issaturated, partially unsaturated or unsaturated (aromatic), and whichconsists of carbon atoms and 1 to 4 heteroatoms independently selectedfrom the group consisting of O, N, NR, and S(O)_(p), and including anybicyclic group in which any of the above-defined heterocyclic rings isfused to a benzene ring. The 5-14 membered heterocyclic system isintended to include a 5, 6, or 7-membered monocyclic or bicyclic or 7,8, 9, 10, 11, 12, 13, or 14-membered bicyclic heterocyclic ring which issaturated, partially unsaturated or unsaturated (aromatic), and whichconsists of carbon atoms and 1 to 4 heteroatoms independently selectedfrom the group consisting of O, N, NR, and S(O)_(p), and including anybicyclic group in which any of the above-defined heterocyclic rings isfused to a benzene ring. The nitrogen and sulfur heteroatoms mayoptionally be oxidized. The heterocyclic ring may be attached to itspendant group at any heteroatom or carbon atom which results in a stablestructure. The heterocyclic rings described herein may be substituted oncarbon or on a nitrogen atom if the resulting compound is stable. Anitrogen in the heterocycle may optionally be quaternized.

Examples of heterocycles include, but are not limited to, pyrimidinyl,phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl,phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl,1,2,3,6-tetrahydropyridyl, piperidonyl, 4-piperidonyl, piperonyl,pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl,pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole,pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl,pyrrolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thia-diazinyl,1,2,3-thiadiazolyl, 1,2,4thiadiazolyl, 1,2,5-thiadiazolyl,1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl,thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl,xanthenyl, octahydro-isoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolidinyl, quinazolinyl, quinolinyl, 4H-quinolizinyl,quinoxalinyl, quinuclidinyl, acridinyl, azocinyl, benzimidazolyl,benzofuranyl, benzothiofuranyl, benzo-thiophenyl, benzoxazolyl,benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl,benzisothiazolyl, benzimidazolinyl, methylenedioxyphenyl, morpholinyl,naphthyridinyl, decahydroquinolinyl, 2H, 6H-1,5,2dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, carbazolyl,4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl,imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl,indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,isothiazolyl and isoxazolyl. Also included are fused ring and spirocompounds containing, for example, the above heterocycles.

Unless otherwise indicated, the compounds provided in the above formulaeI-IV are meant to include pharmaceutically acceptable salts, prodrugsthereof, enantiomers, diastereomers, racemic mixtures thereof,crystalline forms, non-crystalline forms, amorphous forms thereof andsolvates thereof

The term “pharmaceutically acceptable salts” is meant to include saltsof the active compounds which are prepared with relatively nontoxicacids or bases, depending on the particular substituents found on thecompounds described herein. When compounds of the present inventioncontain relatively acidic functionalities, base addition salts can beobtained by contacting the neutral form of such compounds with asufficient amount of the desired base, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable base additionsalts include sodium, potassium, calcium, ammonium, organic amino, ormagnesium salt, or a similar salt. When compounds of the presentinvention contain relatively basic functionalities, acid addition saltscan be obtained by contacting the neutral form of such compounds with asufficient amount of the desired acid, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable acid additionsalts include those derived from inorganic acids like hydrochloric,hydrobromic, nitric, carbonic, phosphoric, partially neutralizedphosphoric acids, sulfuric, partially neutralized sulfuric, hydroiodic,or phosphorous acids and the like, as well as the salts derived fromrelatively nontoxic organic acids like acetic, propionic, isobutyric,maleic, malonic, benzoic, succinic, suberic, fumaric, mandelic,phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric,methanesulfonic, and the like. Also included are salts of amino acidssuch as arginate and the like, and salts of organic acids likeglucuronic or galactunoric acids and the like. Certain specificcompounds of the present invention may contain both basic and acidicfunctionalities that allow the compounds to be converted into eitherbase or acid addition salts.

The neutral forms of the compounds of the present invention may beregenerated by contacting the salt with a base or acid and isolating theparent compound in the conventional manner. The parent form of thecompound differs from the various salt forms in certain physicalproperties, such as solubility in polar solvents, but otherwise thesalts are equivalent to the parent form of the compound for the purposesof the present invention.

As noted above, some of the compounds of formulae I, IA, II, IIA, III,IIIA, IV, IVA, V, VA, VI, and VIA possess chiral or asymmetric carbonatoms (optical centers) or double bonds; the racemates, diastereomers,geometric isomers and individual optical isomers are all intended to beencompassed within the scope of the invention.

Some of the compounds of formulae I, IA, II, IIA, III, IIIA, IV, IVA, V,VA, VI, and VIA can exist in unsolvated forms as well as solvated forms,including hydrated forms. In general, the solvated forms are equivalentto unsolvated forms and are intended to be encompassed within the scopeof the present invention. Certain compounds of the present invention mayexist in multiple crystalline or amorphous forms. In general, allphysical forms are equivalent for the uses contemplated by the presentinvention and are intended to be within the scope of the presentinvention.

In addition to the above-described salt forms, the present inventionalso embraces the compounds of formulae I-VI in a prodrug form. Prodrugsof the compounds described herein are those compounds that readilyundergo chemical changes under physiological conditions to provide thecompounds of the present invention. Additionally, prodrugs can beconverted to the compounds of the present invention by chemical orbiochemical methods in an ex-vivo environment. For example, prodrugs canbe slowly converted to the compounds of the present invention whenplaced in a transdermal patch reservoir with a suitable enzyme orchemical reagent.

The novel compounds of the present invention may be prepared in avariety of ways well known to one skilled in the art of organicsynthesis. The compounds of the present invention can be synthesizedusing the methods as hereinafter described below, together withsynthetic methods known in the art of synthetic organic chemistry orvariations thereon as appreciated by those skilled in the art. Preferredmethods include, but are not limited to, those described below. Theentire contents of all references cited herein are hereby incorporatedby reference.

The novel compounds of this invention may be prepared using the reactionpathways and techniques as described below.

The inventive compounds, and the salts, solvates, and prodrugs thereof,may be prepared by employing the techniques available in the art usingstarting materials that are readily available. Exemplary methods ofpreparing the inventive compounds are described below. In the followingschemes, unless otherwise indicated, Z, P, R, R¹, R², R³, R⁴, D, Q, L,T, X, and Y, etc. are as previously defined herein.

The inventive compounds of the formula I and IA wherein Z is hydroxamicacid group can be prepared by reacting a compound of the formula 1a(where Z is a carboxylic acid) with hydroxylamine in the presence of asuitable peptide coupling reagent. Illustrative examples of suitablecoupling agents including 1,1′-carbonyl-diimidazole,N-(dimethylaminopropyl)-N′-ethyl carbodiimide,benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluoro-phosphate(“PyBOP”), or propanephosphonic anhdride in an inert polar solvent, suchas dimethylformamide (“DMF”).

Alternatively, the coupling reactions described above can be carried outwith compounds of formula 1a and oxygen-protected compounds ofhydroxylamine (i.e., a suitable protecting group known to those skilledin the art, such as benzyl, t-butyl, t-butyldimethylsilyl, ort-butyldiphenylsilyl, and/or described in T. W. Green and P. G. M. Wuts,Protective Groups in Organic Synthesis (1991)) to give compounds offormula 2/Deprotection of compounds of the formula 2 provides compoundsof formula (I). Suitable methods of deprotecting compounds of theformula 2 are known in the art, for example, as described in T. W. Greenand P. G. M. Wuts, Protective Groups in Organic Synthesis (1991).

Compounds of the formula 1a can be prepared by alkaline hydrolysis ofthe corresponding ester 1b (where alkyl is a suitable group such asmethyl, ethyl, allyl, benzyl- or t-butyl) using a suitable aqueous base,such as lithium hydroxide, sodium hydroxide, or potassium hydroxide,preferably in a homogeneous aqueous-organic solvent mixture.Alternatively, these compounds can also be prepared by acid hydrolysisof the corresponding ester using a suitable aqueous acid, such ashydrochloric acid in aqueous dioxane, at a suitable temperature. Othermethods recognizable by those skilled in the art as suitable forconverting esters to acids can also be employed, such as hydrogenolysisof the benzyl ester using hydrogen and palladium on carbon,acid-promoted cleavage of t-butyl esters under anhydrous conditions, andpalladium-catalyzed cleavage of allyl esters.

Alternatively, compounds of formula I can also be prepared from theester compound of formula 1b via several routes known in the literature,such as by treatment of the esters 1b with hydroxylamine under basicconditions such as KOH or NaOMe in solvents such as methanol, byconverting the esters 1b to oxygen-protected hydroxyamic acid undersimilar conditions followed by subsequent deprotection as previouslydescribed or by using Weinreb's trimethylaluminum reaction conditions(J. I. Levin, E. Turos, S. M. Weinreb, Syn. Comm. 1982, 12, 989) orRoskamp's bis[bis(trimethylsilyl)amido]tin reagent (W.-B. Wang, E. J.Roskamp, J. Org. Chem. 1992, 57, 6101). The compounds of formula 1b withdifferent substituents R, R¹, and R² can be synthesized following avariety of literature routes by funtionalizing the corresponding ring Acompounds of formula 3 or 16 as outlined in Scheme 2-5. Onerepresentative approach as shown in Scheme 2 is selective reduction ofthe ketone of formula 3 with appropriate metal-hydride system known inart, such as sodium borohydride in an aprotic solvent. Alkylation of thealcohol compound of formula 4 with the desired alkyl halide or alkylsulfonate under basic conditions as reviewed in “Comprehensive OrganicTransformations, A Guide to Funtional Group Preparations” (R. C. Larock,Wiley-VCH, 1999) provides ether compounds of formula 5. Alternatively,ether compound 5 may be prepared by Mitsnobu reaction as known in theart. The alcohol compounds of formula 4 can also be converted tocarbonates of formula 6 or carbamates of formula 7 via severalapproaches known in the literatures, such as by reacting alcohol offormula 4 with desired chloroformates or carbamyl chlorides in thepresence of a base, or by treatment of the alcohol of formula 4 withcarbonyl diimidazole or p-nitrophenyl chloroformate followed by reactionof the resultant active carbamate or carbonate with desired alcohols oramines

Alternatively, the ketone of formula 3 could be subjected to reductiveamination with desired amines to afford the amines of formular 8 (Scheme3) following a variety of literature procedures such as reviewed in“Comprehensive Organic Synthesis” (B. M. Trost, I. Fleming, Eds.Pergamon, 1991, Vol 8, Part 1.2, P25). The amines of formula 8 couldthen be further transformed into amides of formula 9, sulfonamides offormula 10, carbamates of formula 11, or ureas of formula 12 usingmethods known in the art.

Alternatively, the ketones of formula 3 could be subjected to carbonylhomologation as outlines in Scheme 4 and reviewed in “ComprehensiveOrganic Transformations, A Guide to Functional Group Preparations” (R.C. Larock, Wiley-VCH, 1999). For example, treatment of compounds offormula 3 with trimethylsilyl cyanide in the presence of tin (II)chloride followed by acid hydrolysis (Syn. Commun. 1982, 12, 763), or,by reacting with 1,3-dithianes anion followed by acid catalyzedhydrolysis (Tetrahedron Lett. 1988, 29, 1493) or mercury salt catalyzedhydrolysis (J. Org. Chem. 1991, 56, 4499). Where desired, compounds offormula 3 can also be subjected to Wittig and related reactionconditions followed by catalytic hydrogenation to reduce the resultantdouble bond to provide compounds of formula 13 as shown in Scheme 4(Comprehensive Organic Synthesis, B. M. Trost, I. Fleming, Eds.Pergamon, 1991, Vol 1, Part 3.1, P729). The esters of formula 13 canthen be transformed to amides of formula 14 using the methods describedin Scheme 1. On the other hand, the esters of formula 13 can beconverted to aldehydes of formula 15 by methods recognizable by thoseskilled in the art; for example, such as by selective hydrolysis of theester followed by reduction of the resultant acid to form thecorresponding alcohols with borane, then oxidation of the alcohol toform the corresponding aldehydes. The latter aldehydes can be furtherfunctionalized using reaction methodology in an analogous manner asthose described in Schemes 2 and 3.

Alternatively, ketone of formula 3 can be subjected to Grignard orrelated lithium anion reaction conditions to generate a tertiary alcoholas depicted in Scheme 5. Or, ketone of formula 3 can also be subjectedto reactions with allyltrimethylsilane catalyzed by lewis acid togenerate corresponding tertiary alcohol. The tertiary alcohols can befurther derivatized as described in Scheme 2. Alternatively, the ketoneof formula 3 can also be subjected to Wittig reaction conditions tofurnish a vinyl compound which can be oxidized to an epoxide (Scheme 5).The epoxide can be opened by HO(CR^(d)R^(d1))_(r)M orHN(R^(a))(CR^(d)R^(d1))_(r)M to afforded vicinal diol mono-ether orvicinal amino alcohol, respectively. The latter can be further modifiedas described in Scheme 2 and 3 when (CR^(d)R^(d1))_(r)M is hydrogen.

When the ring A is an aza-ring, as shown in formula 16 in Scheme 6, thecompounds can be converted directly to formula 17, 18, 19, 20 and 21,for example by treatment with a suitable alkylating or acylating agent,such as an alkyl halide, sulfonyl chloride, carboxylic acid chloride,chloroformate or carbamyl chloride, respectively, in a suitable solventat an appropriate temperature. Alternatively, the compounds of formula16 can also be alkylated to yield formula 22, which could then befurther functionalized as described in Scheme 4.

The ring A compounds of formula 3 and 16 can be synthesized using themethods outlined in Scheme 7-15, together with synthetic methods knownin the art of synthetic organic chemistry, or variations therein asappreciated by those skilled in the art. Preferred methods include, butare not limited to, those described below.

The 5-oxo-piperidine of formula 30 and 31 can be prepared using theprocedures described in Scheme 7. L-Aspartic acid β-tert-butyl estermonohydrate is treated with 2 equivalents of benzyl bromide in thepresence of DBU in toluene to afford mono-benzyl amine 23. Alkylation of23 with 1-chloro-2-chloromethyl-1-propene gives allyl chloride 24, whichis converted to the corresponding allyl iodide 25 by the treatment withsodium iodide in acetone. The latter is reacted with LiHMDS to yield thepiperidine ring compound 26. After changing the benzyl protection in 26to Cbz protection, the resultant alkene 27 was subjected toozonelization to provide the ketone compound 28. The latter can bede-protected by catalyzed hydrogenation and then reacts with anappropriate amines to generate the corresponding ketone 30.Alternatively, the amino acid 29 can be subjected to coupling withbenzyl protected hydroxylamine in the presence of BOP to furnish benzylprotected hydroxyamide 31, which could then be converted to ketone 32.

Cyclohexanones of formula 40 and 41 can be synthesized as shown inScheme 8. The optically pure(1S,2R)-1-methyl-cis-1,2,3,6-tetrahydrophthalate is transferred totert-butyl ester 33 followed by hydrolysis of the methyl ester to givethe corresponding acid 34. The latter reacts with potassiumtert-butoxide to yield the trans-compound 35. Treatment of 35 withiodine affords lactone 36. After removal of the iodide by treatment withtris(trimethylsilyl)silane, the lactone 37 is treated with benzylalcohol to provide a differentiated bis-ester 38, which can beoxidazided to give ketone 39 under Dess-Martin oxidation or Swernoxidation conditions. Ketone 39 can then be transformed selectively toketone 40 or 41 by deprotection and coupling with desired amines,respectively. Alternatively, ketone 39 can be prepared fromcorresponding cyclohexene directly via Wacker oxidation.

The cyclopentanones of formula 46 and 47 can be synthesized asillustrated in Scheme 9. The optically pure(1S,2R)-1-methyl-cis-1,2,3,6-tetrahydrophthalate is converted totrans-isomer 42, followed by treatment with 2-methylpropene in thepresence of sulfuric acid to furnish diester 43. The cyclohexene 43 isoxidized to the bis-acid and cyclized to the ketone 45 (for a relatedexample refer to: Gais et al. J. Org. Chem. 1989, 54, 5115). The ketone45 is then converted to 46 or 47 as shown in Scheme 9.

The tetrahydropyran compounds of formula 54 and 55 can be preparedstarting from (S)-(+)-2,2-dimethyl-5-oxo-1,3-dioxolane-4-acetic acid asillustrated in Scheme 10. After being protected as benzyl ester 48, thedioxolane ring is hydrolyzed to give methyl ester 49. Reaction of 49with 1-chloro-2-chloromethyl-1-propene under basic conditions providesallyl chloride 50, which is converted to iodide 51. Treatment of 51 withLiHMDS yields tetrahydropyran 52. The latter can then be ozonized togive ketone 53 and subsequently 54 and 55 as shown in Scheme 10.

The tetrahydrofuran compounds of formula 62 and 63 can be obtained asdescribed in Scheme 11. Protection of hydroxy compound 49 as silyl ether56 followed by reaction of the latter with allyl iodide in the presenceof KHMDS generates compound 57 as a major diastereoisomer. Afterdeprotection, the hydroxy compound 58 is treated with iodine to furnish59. Iodide 59 can then be converted to aldehyde 61 via an alcoholintermediate 60. The coupling of the aldehyde 60 with the desired aminesas shown in Scheme 11 then provides tetrahydrofuran compounds of formula62 and 63.

A series of trans-2,3-pyrrolidinedicarboxylate of formula 68 and 69 canbe prepared using the sequence shown in Scheme 12. Alkylation ofCbz-protected L-aspartic acid ester with allyl iodide using LiHMDS as abase followed by chromatography to separate the two produceddiastereoisomers yields the desired syn-diastereoisomer 64. Ozonolysisof 64 converts it to an aldehyde 65. Hydrogenation of 65 leads to a ringclosure to generate a pyrrolidine 66. Derivatization at the dicarboxylicacid as described in Scheme 7 affords compounds of formula 68 and 69.

The 5-formyl pyrrolidine compounds of formula 76 and 77 can be obtainedin analogue to the preparation of 5-formyl tetrahydrofuran as describedin Scheme 10 and is illustrated in Scheme 13.

A series of compounds of formula 81 and 82 are prepared following thesequence outlined in Scheme 14. Pyrrolidine 79 is prepared following adipolar addition procedure documented in the literature (M. Joucla, J.Mortier, Chem. Commun. 1985, 1566). After Boc-pretection of thepyrrolidine, compound 80 can be transformed to the desired compounds offormula 81 and 82, respectively.

Compounds of formula (I) wherein ring A is piperidine (shown below) canbe prepared following literature procedures (C.-B. Xue, X. He, J.Roderick, R. L. Corbertt, C. P. Decicco, J. Org. Chem. 2002, 67, 865).

It should be noted that the synthesis shown above could be modified toconstruct the R, R¹ and R² before coupling of ring A with amines to formthe D-E-G-Q-L-T-X-Y fragment. One stereomer of a compound of formula (I)may display better activity compared with the others. Thus the followingstereochemistries are considered to be a part of the present invention.

When required, separation of the racemic material can be achieved byHPLC using a chiral column or by a resolution using a resolving agentsuch as camphonic chloride as documented in literature (S. H. Wilen,“Tables of Resolving Agents and Optical Resolutions, 1972) or usingenantiomerically pure acids and bases. A chiral compounds of Formula (I)may also be directly synthesized using a chiral catalyst or a chiralligand (E. Jacobsen, Acc. Chem. Res. 2000, 33, 421) or using otherenantio- and diastereo-selective reactions and reagents known to oneskilled in the art of asymmetric synthesis.

For example, the axial hydroxy compound shown in Scheme 15 could beprepared by reduction with L-Selectride in THF. The axial and equatorialhydroxy isomers were obtained in a ratio of 15:1. On the other hand, theequatorial hydroxy compound could be obtained, by reduction with sodiumboronhydride in methanol, as a separable 11:1 mixture of equatorial andaxial diastereoisomers.

The alkene compound in Scheme 16 could be selective reduced to axialisomer in 92% d.e. under homogeneous conditions.

Intermediates of the present invention with a formula -Q-Y (P, whereinE, G, L, T, and X are absent) can be synthesized using strategiesloosely grouped into three types: synthesis in which the ring Q isattached to the ring Y through the ring nitrogen; carbon-carbon bondformation between the two cyclic structures; and synthesis in which thering Q is formed during synthesis. This is illustrated in Scheme 15-18using aryl piperazine and aryl piperidine and aryl pyrrolidine asexamples, respectively (wherein Q is piperazine, piperidine orpyrroline; and Y is aryl).

Aryl piperazines can be prepared by reacting Boc-piperazine with avariety of boronic acid under the catalysis of copper (II) acetate(Combs, A. P.; Tadesse, S.; Rafalski, M.; Hague, T. S.; Lam, P. Y. S.Journal of Combinatorial Chemistry 2002, 4, 179), or by reacting with avariety of aryl halide using Hartwig's catalyst (Louie, J; Hartwig, J.F. Tetrahedron Lett. 1995, 36, 3609). After removal of the Boc group,compound 90 can be coupled with ring A compounds to furnish compounds offormula 91 (Scheme 17). It should be noted that the arylpiprazine canalso be prepared through classical ring closure of appropriatelysubstituted anilines and bis(2-chloroethyl)amine hydrochloride in thepresence of base (E. Mishani, et. al. Tetrahedron Lett. 1996, 37, 319),or through direct nucleophilic aromatic substitution of the piperazine(S. M. Dankwardt, et al, Tetrahedron Lett. 1995, 36, 4923).

Aryl piperidines such as 36 may be synthesized as described in Scheme18. tert-Butoxycarbonylpiperid-4-one is converted to the enol triflate92 using LDA and N-phenyltrifluoromethanesulfonamide. Suzuki-typecoupling with arylboronic acid then produces the aryltetrahydropyridine94 (M. G. Bursavich, D. H. Rich, Org. Lett. 2001, 3, 2625). Compound 94can also be prepared from Suzuki-type coupling of aryl halide with enolboronate 93. After deprotection, compound 95 can be converted to formula96. The aryltetrahydropyridine can be reduced to saturated arylpiperidine under catalytic hydrogenation condition where desired. Itshould be noted that compound 94 can also be prepared though classicdirect nucleophilic addition of aryl anion to a piperidone followed bydehydration of the resultant alcohol compound.

Alternatively, aryl piperidine derivatives can be prepared by couplingof 4-bromopyridine with a boronic acid using Pd(PPh₃)₄ as a catalystfollowed by hydrogenation as shown in Scheme 19.

Phenylpyrrolidine 100 can be prepared as illustrated in Scheme 20.Optical pure (R)-phenylsuccinic acid is reduced to diol 97 followed bymesylation to afford di-mesylate 98. Treatment of 98 with benzylamine inthe presence of triethylamine provides pyrrolidine 99, which afterhydrogenation provides 100. Alternatively, refluxing of(R)-phenylsuccinic acid in acetyl chloride affords the correspondinganhydride 102. After treatment with ammonia and reflux in acetylchloride again, imide 103 is obtained and then subjects to LAH reductionto give the phenylpyrrolidine 100. Reaction of 100 with ring A compoundgenerated formula 101. It should be noted that aryl pyrrolidinecompounds also can be synthesized through Suzuki-type coupling via anenol triflate or enol boronate intermediates as described in Scheme 16.It also can be prepared through classic direct nucleaphilic addition ofaryl anion to a pyrrolidone followed by dehydration of the resultantalcohol compound and then asymmetric hydrogenation.

Intermediates of the present invention with a formula -Q-L-T-Y (P,wherein E, G, and X are absent) can be synthesized as exemplified inScheme 21 (wherein Q is phenyl, L is oxygen, T is methylene, and Y ismethylquilonine). The starting material 2-methylquilonine is convertedto alcohol 104 followed by treatment with thionyl chloride to yield 105.Reaction of 105 with phenol 106 under basic conditions provides 107. Thelatter can be de-protected by treating with TFA to afford aniline 108,which can then be transformed to intermediate of formula 109.

Other possible P groups (wherein -D-E-G-Q-L-T-X-Y are as previouslydefined herein) can be prepared using methodologies known in the art.Specific examples of methods used to prepare the inventive compounds aredescribed below along with illustrative preferred embodiments of theinventive compounds of the formulae (I), (II), and (III) or theirpharmaceutically acceptable prodrugs, salts or solvates.

The following specific examples are intended to be illustrative of theinvention and should not be construed as limiting the scope of theinvention as defined by the appended claims. These examples includepreferred embodiments of the inventive compounds.

EXAMPLES

Reagents and solvents used below can be obtained from commercial sourcessuch as Aldrich Chemical Co. (Milwaukee, Wis., USA). Mass spectrometryresults are reported as the ratio of mass over charge. In tables, asingle m/e value is reported for the M+H (or, as noted, M−H) ioncontaining the most common atomic isotopes. Isotope patterns correspondto the expected formula in all cases.

Example 1(2S,3S,5R)-2-{[4-(4-cyano-2-methylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-N-hydroxy-5-[(3R)-3-hydroxypyrrolidin-1-yl]piperidine-3-carboxamidePart 1

To a mixture of L-aspartic acid β-tert-butyl ester monohydrate (22 g,106 mmol) and benzyl bromide (35 g, 205 mmol) in toluene (600 mL) wasadded DBU (33 g, 217 mmol) dropwise, at 0° C., under nitrogen. Themixture was allowed to warm to rt and stirred overnight. The crudereaction mixture was filtered through a glass filter and concentratedunder reduced pressure. The residue was purified by Combiflash (hexaneand ethyl acetate:gradient 0 to 10% in 12 min) to afford 12.1 g (30.9%)of (2S)-benzylamino-succinic acid 1-benzyl ester 4-tert-butyl ester. MS(ESI): 370 (M+H⁺).

Part 2

A mixture of (2S)-benzylamino-succinic acid 1-benzyl ester 4-tert-butylester (12.1 g, 32.6 mmol), K₂CO₃ (14 g, 3 equiv.), NaI (3.0 g, 20 mmol)and 3-chloro-2-chloromethyl-1-propene (5.1 g, 40.8 mmol) in MeCN (150mL) was stirred at 81° C. for 16 h. After cooling, the reaction mixturewas filtered and the filtrate was concentrated under reduced pressure.Purification by Combiflash (hexane and ethyl acetate: gradient 0 to 8%during 12 min) afforded(2S)-[benzyl-(2-chloromethyl-allyl)-amino]-succinic acid 1-benzyl ester4-tert-butyl ester (8.7 g, 58%). MS (ESI): 458 (M+Na⁺).

Part 3

A mixture of the chloride made above (8.7 g, 19.0 mmol) and NaI (8.0 g,53.3 mmol) in acetone (100 mL) was stirred at rt overnight. Theheterogeneous mixture was filtered and the filtrate was concentratedunder reduced pressure. The residue was treated with methylene chlorideand filtered through a pad of silica gel to give the correspondingiodide compound (9.2 g, 88.2%). MS (ESI): 550 (M+H⁺)

Part 4

To a solution of the iodo-compound made above (9.2 g, 16.76 mmol) inanhydrous THF (50 mL) was added dropwise LiHMDS (1.0 M in THF, 20.2 mL)at −78° C., under nitrogen, during a period of 30 min. The mixture wasstirred at −78° C. for 1 h, and then was allowed to warm to −30° C.during a period of 3 h. The reaction mixture was quenched with 10%citric acid (10 mL), diluted with brine (100 mL) and extracted withethyl acetate (4×75 mL). The combined organic layers were dried overMgSO₄ and concentrated under reduced pressure. The residue was purifiedusing Combiflash (eluting with hexane and ethyl acetate:gradient 0 to 5%during 12 min) to give(2S,3S)-1-benzyl-5-methylene-piperidine-dicarboxylic acid 2-benzyl ester3-tert-butyl ester (3.45 g, 48.9%). MS (ESI): 422 (M+H⁺)

Part 5

A mixture of the N-benzylpiperidine made above (2.3 g, 5.46 mmol) andbenzyl chloroformate (3 mL) was stirred at 65° C. for 28 h. The excessof the benzyl chloroformate was removed under reduced pressure and theresidue was purified by Combiflash (hexane and ethyl acetate:gradient 0to 10% during 12 min) to give the corresponding N-Cbz protectedpiperidine compound (1.40 g, 52.6%). MS (ESI): 488 (M+Na⁺); 366(M+2H⁺—COO(t-Bu)).

Part 6

Ozone was passed through a solution of the alkene compound made above(6.0 g, 12.9 mmol) in methylene chloride (250 mL), at −78° C., until thecolor of the solution remained blue. After the addition of dimethylsulfide (1.2 mL. 16.1 mmol), the resultant mixture was allowed to warmto rt and stirred overnight. The mixture was then concentrated underreduced pressure, redissolved in methylene chloride and washed withbrine. After drying the organic layer with MgSO₄ and removal of thevolatiles in-vacuo, the crude product was purified by chromatography(hexane and ethyl acetate:gradient 0 to 30%) to give(2S,3S)-5-oxo-piperidine-tricarboxylic acid 1,2-dibenzyl ester3-tert-butyl ester (5.2 g, 86.2%). MS (ESI): 468 (M+H⁺).

Part 7

A mixture of (R)-pyrrolinol (140 mg, 1.60 mmol) and the ketone madeabove (250 mg, 0.53 mmol) in of methylene chloride (5 mL) was treatedwith NaBH(OAc)₃ (339 mg, 1.60 mmol) and stirred at rt overnight. Thereaction was quenched with satd. NaHCO₃ and extracted with methylenechloride. The organic layers were combined and dried with sodiumsulfate. After evaporation of the solvent, the resultant residue waspurified by flash chromatography (eluting with 0 to 10% MeOH in CH₂Cl₂)to afford a mixture of (R)-[(R)-hydroxypyrrolidine] substitutedpiperidine compound (115 mg, 39.9%) and its diastereoisomer,(S)-[(R)-hydroxypyrrolidine] substituted piperidine compound (64 mg,22.2%). MS (ESI): 539 (M+H⁺).

Part 8

A solution of the (R)-[(R)-hydroxypyrrolidine] substituted isomer madeabove (230 mg, 0.43 mmol) in methanol (5 mL) was hydrogenated in thepresence of 10% Pd/C, under balloon pressure of hydrogen, overnight. Theheterogeous reaction mixture was filtered through a pad of celite andconcentrated under reduced pressure to afford the corresponding desiredamino acid (133 mg, 99%), which was used directly in the couplingreaction in Part 13.

Part 9

To a solution of tert-butyl-4-oxopiperidine-1-carboxylate (5.21 g, 26.16mmol) in anhydrous THF (26 mL) was added dropwise LiHMDS (1.0 M in THF,28.7 mL, 28.7 mmol) at −78° C., under nitrogen. After 20 min, a solutionof N-phenyl trifluoromethanesulfonimide (10.0 g, 27.99 mmol) in THF (26mL) was added and the reaction was allowed to gradually warm to 0° C.and stirred for 3 h. The reaction was quenched with a minimum amount ofsaturated NaHCO₃ and the resultant mixture was concentrated underreduced pressure. Flash chromatography on neutral Al₂O₃ afforded thedesired enol triflate (8.67 g, 100%).

Part 10

A flask charged with bis(pinacolato)diboron (3.37 g, 13.28 mmol), sodiumacetate (2.97 g, 36.22 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II)](PdCl₂dppf) (0.296 g, 0.36 mmol), dppf (0.20 g, 0.36 mmol) and1,4-dioxane (30 mL) was flushed with nitrogen. To the flask was added asolution of the enol triflate (4.0 g, 12.07 mmol) in 1,4-dioxane (30 mL)and the resultant mixture was stirred at 80° C. overnight. The reactionwas quenched by the dropwise addition of water and aqueous layer wasextracted with ethyl acetate. The combined organic layers were washedwith brine, dried over MgSO₄ and concentrated under reduced pressure.The residue was purified by flash chromatography, eluting with 0 to 10%ethyl acetate in hexane, to give the boronate as a white wax-like solid(3.14 g, 84%). MS (ESI): 210 (M+2H⁺-Boc), 332 (M+Na⁺).

Part 11

To a nitrogen flushed flask containing the above boronate (2.0 g, 6.47mmol), K₂CO₃ (2.68 g, 19.40 mmol) and PdCl₂dppf (317 mg, 0.38 mmol) wasadded a solution of 4-bromo-3-methylbenzonitrile (1.40 g, 7.12 mmol) inDMF (33 mL). The resultant mixture was heated to 80° C. and vigorouslystirred overnight under nitrogen. The reaction was quenched with waterand extracted with ethyl acetate. The combined organic layers werecombined and washed with brine, dried (MgSO₄) and concentrated underreduced pressure. The residue was purified by flash chromatography,eluting with 0 to 30% ethyl acetate in hexane, to provide the desiredbiaryl product (1.5 g, 77.7%).

Part 12

The above tetrahydropyridine compound (1.3 g, 4.36 mmol) was treatedwith HCl/dioxane solution (4N, 5 mL) at rt for 1 h. The mixture wasconcentrated under reduced pressure to afford3-methyl-4-(1,2,3,6-tetrahydropyridin-4-yl)-benzonitrile HCl salt (1.02g, 100%). MS (ESI): 199 (M+H⁺).

Part 13

A mixture of the amino acid made in part 8 (53 mg, 0.17 mmol),3-methyl-4-(1,2,3,6-tetrahydropyridin-4-yl)-benzonitrile HCl salt (40mg, 0.17 mmol) and BOP (82 mg, 0.19 mmol) in DMF (0.2 mL) was treatedwith diisopropylethylamine (0.065 mL, 0.37 mmol) at rt, under nitrogen,for 2 h. The reaction was quenched with saturated NaHCO₃ and extractedwith ethyl acetate. The combined organic layers were washed with brine,dried over MgSO₄ and concentrated under reduced pressure. The resultantresidue was used directly in next step without further purification. MS(ESI): 495 (M+H⁺).

Part 14

The above-titled compound was dissolved in CH₂Cl₂ (1 mL) and treatedwith TFA (1 mL) at rt for 3 h. The mixture was concentrated underreduced pressure to afford the crude piperidine 3-carboxylic acid, whichwas used directly in next step without purification. MS (ESI): 439(M+H⁺).

Part 15

A mixture of the above crude piperidine 3-carboxylic acid was dissolvedin DMF (0.2 mL) and to this was added sequentially: hydroxylamine HClsalt (19 mg, 0.27 mmol), BOP (73 mg, 0.16 mmol), anddiisopropylethylamine (0.072 mL, 0.41 mmol) at rt, under nitrogen. After2 h, the reaction mixture was applied directly on RP-HPLC to provide thetitle compound as a TFA salt (29 mg, 35% in 3 steps). MS (ESI): 454.1(M+H⁺).

Example 2(2S,3S)-2-{[4-(4-cyano-2-methylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-5-(2-{[2-(dimethylamino)ethyl]amino}-2-oxoethyl)-N-hydroxypiperidine-3-carboxamidePart 1

To a flask charged with methyl(triphenylphosphoranylidene)acetate (787mg, 2.35 mmol) was added a solution of(1,2S,3S)-5-oxo-piperidine-tricarboxylic acid 1,2-dibenzyl ester3-tert-butyl ester (500 mg, 1.07 mmol) in toluene (5.4 mL). Theresultant mixture was heated to reflux and stirred overnight. Aftercooling the reaction mixture to rt, the volatiles were removed underreduced pressure. Purification by flash chromatography, eluting with 0to 30% ethyl acetate in hexane, afforded the Wittig products as aseparable trans- and cis-mixture (257 mg, 45.9%, 7:1, stereochemistrynot determined). MS (ESI): 546 (M+Na⁺).

Part 2

A solution of the alkene mixture (257 mg, 0.49 mmol) in methanol (3 mL)was hydrogenated in the presence of 10% Pd/C (60 mg), under balloonpressure of hydrogen, for 2 h. The heterogeneous mixture was filteredthrough a pad of celite and the volatiles were removed under reducedpressure to afford(5)-methoxycarbonylmethyl-piperidine-(2S,3S)-dicarboxylic acid3-tert-butyl ester (148 mg, 100%) as an inseparable mixture ofdiastereoisomers. MS (ESI): 302 (M+H⁺).

Part 3

The amino acid made above (148 mg, 0.49 mmol) was coupled with3-methyl-4-(1,2,3,6-tetrahydropyridin-4-yl)-benzonitrile HCl salt (115mg, 0.49 mmol) as described in Example 1, Part 13 to provide thecorresponding amide compound. MS (ESI): 482 (M+H⁺).

Part 4

To a solution of the crude product made above (115 mg, 0.49 mmol) in THF(1 mL) was added a solution of LiOH solution (3 N, 0.049 mL, 1.47 mmol)at 0° C. The resultant mixture was stirred at rt for 1 h, then 3 mL of1N HCl was added at 0° C. The mixture was lyophilized to afford(5)-carboxylmethyl-(2S)-[4-(4-cyano-2-methyl-phenyl)-3,6-dihydro-2H-pyridine-1-carbonyl]-piperidine-(3S)-carboxylicacid tert-butyl ester lithium salt, which was used directly in thefollowing step. MS (ESI): 468 (M+H⁺).

Part 5

The lithium salt made above (50 mg, 0.099 mmol) was coupled withN,N-dimethylethylenediamine (0.011 mL, 0.099 mmol) as described inExample 1, Part 13 to provide the corresponding amide compound. MS(ESI): 538 (M+1⁺).

Part 6

Using procedures analogous to Part 14 and Part 15 in Example 1, thetert-butyl ester from above was converted to the desired hydroxyamide asan inseparable mixture of diastereoisomers at C-5 of the piperidine ring(3.1 mg). MS (ESI): 497 (M+1⁺).

Example 3(2S,3S,5S)-2-{[4-(4-cyano-2-methylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-N-hydroxy-5-{2-[(3R)-3-hydroxypyrrolidin-1-yl]-2-oxoethyl}piperidine-3-carboxamideand(2S,3S,5R)-2-{[4-(4-cyano-2-methylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-N-hydroxy-5-{2-[(3R)-3-hydroxypyrrolidin-1-yl]-2-oxoethyl}piperidine-3-carboxamide

The two titled compounds were prepared using procedures analogous tothose for Example 2. The two diastereoisomers were separated by RP-HPLC.

Example 4(2S,3S,5S)-2-{[4-(4-cyano-2-methylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-N-hydroxy-5-(2-morpholin-4-yl-2-oxoethyl)piperidine-3-carboxamideand(2S,3S,5R)-2-{[4-(4-cyano-2-methylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-N-hydroxy-5-(2-morpholin-4-yl-2-oxoethyl)piperidine-3-carboxamide

The two titled compounds were prepared using procedures analogous tothose for Example 2. The two diastereoisomers were separated by RP-HPLC.

Example 5(2S,3S,5S)-2-{[4-(4-cyano-2-methylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-N-hydroxy-5-[2-(4-hydroxypiperidin-1-yl)-2-oxoethyl]piperidine-3-carboxamideand(2S,3S,5R)-2-{[4-(4-cyano-2-methylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-N-hydroxy-5-[2-(4-hydroxypiperidin-1-yl)-2-oxoethyl]piperidine-3-carboxamide

The two titled compounds were prepared using procedures analogous tothose for Example 2. The two diastereoisomers were separated by RP-HPLC.

Example 6(2S,3S,5R)-2-{[4-(4-cyano-2-methylphenyl)piperazin-1-yl]carbonyl}-N-hydroxy-5-[(methoxyacetyl)(methyl)amino]piperidine-3-carboxamideand(2S,3S,5S)-2-{[4-(4-cyano-2-methylphenyl)piperazin-1-yl]carbonyl}-N-hydroxy-5-[(methoxyacetyl)(methyl)amino]piperidine-3-carboxamidePart 1

A mixture of methylamine hydrochloride (216.6 mg, 3.21 mmol) and5-oxo-piperidine-(2S,3S)-1,2,3-tricarboxylic acid 1,2-dibenzyl ester3-tert-butyl ester (500 mg, 1.07 mmol) in 1,2-dichloroethane (3.6 mL)was treated with NaBH(OAc)₃ (680 mg, 3.21 mmol) and stirred at rtovernight. The reaction was quenched with saturated NaHCO₃ and extractedwith ethyl acetate. The combined organic layers were dried overmagnesium sulfate and concentrated in-vacuo to afford the(5)-methylamino-piperidine-(1,2S,3S)-tricarboxylic acid 1,2-dibenzylester 3-tert-butyl ester, which was used directly in the following stepwithout further purification. MS (ESI): 483.1 (M+H⁺).

Part 2

To a solution of the above crude product in CH₂Cl₂ (3.6 ml) was addedmethoxyacetyl chloride and Et₃N. After vigorously stirring the reactionmixture at rt for 30 min, the volatiles were removed in-vacuo.Purification by flash chromatography (0-10% ethyl acetate in hexane)afforded(5R)-[(2-methoxy-acetyl)-methyl-amino]-piperidine-(1,2S,3S)-tricarboxylicacid 1,2-dibenzyl ester 3-tert-butyl ester (190 mg) and(5S)-[(2-methoxy-acetyl)-methyl-amino]-piperidine-(1,2S,3S)-tricarboxylicacid 1,2-dibenzyl ester 3-tert-butyl ester (170 mg) as purediastereoisomers. The less polar diastereoisomer was assigned to be the(5R)-isomer and was the more polar diasteoisomer. MS (ESI): 555.1(M+H⁺).

Part 3

A solution of(5R)-[(2-methoxy-acetyl)-methyl-amino]-piperidine-(1,2S,3S)-tricarboxylicacid 1,2-dibenzyl ester 3-tert-butyl ester (190 mg, 0.343 mmol) inmethanol (2 mL) was hydrogenated in the presence of 10% Pd/C (40 mg),under balloon pressure of hydrogen, for 1 h. The heterogeneous mixturewas filtered through a pad of celite and the volatiles were removed toafford(5R)-[(2-methoxy-acetyl)-methyl-amino]-piperidine-(2S,3S)-dicarboxylicacid 3-tert-butyl ester (102.4 mg, 90%) as a white solid. MS (ESI):331.2 (M+H⁺).

(5S)-[(2-methoxy-acetyl)-methyl-amino]-piperidine-(2S,3S)-dicarboxylicacid 3-tert-butyl ester was made in an analogous manner.

Part 4

To a nitrogen flushed flask containing PdCl₂dppf (65.8 mg, 0.081 mmol),dppf (44.6 mg, 0.081 mmol) and 4-bromo-3-methylbenzonitrile (631 mg,3.22 mmol) in THF (5 mL) at −78° C. was added tert-butyl1-piperazinecarboxylate (500 mg, 2.68 mmol) as a solid. The resultantmixture was heated to 100° C. and vigorously stirred overnight undernitrogen. The reaction was quenched with water and extracted with ethylacetate. The combined organic layers were washed with brine, dried(MgSO₄) and concentrated under reduced pressure. The residue waspurified by flash chromatography (eluting with 0 to 30% ethyl acetate inhexane) to afford 4-(4-cyano-2-methyl-phenyl)-piperazine-1-carboxylicacid tert-butyl ester (702 mg, 86.9%). MS (ESI): 302.0 (M+H⁺).

Part 5

The titled compound above (702 mg, 2.33 mmol) was dissolved in CH₂Cl₂ (2mL) and treated with TFA. (2 mL) After stirring the reaction mixture atrt for 1 h, the volatiles were removed under reduced pressure to provide4-(4-cyano-2-methyl-phenyl)-piperazine TFA salt.

Part 6

A mixture of(5R)-[(2-methoxy-acetyl)-methyl-amino]-piperidine-(2S,3S)-dicarboxylicacid 3-tert-butyl ester (69 mg, 0.21 mmol),4-(4-cyano-2-methyl-phenyl)-piperazine TFA salt (89.7 mg, 0.21 mmol) andBOP (102 mg, 0.23 mmol) in anhydrous DMF (0.4 mL) was treated withdiisopropylethylamine (0.12 mL, 0.69 mmol) at rt, under nitrogen, for 2h. The reaction was quenched with saturated NaHCO₃ and extracted withethyl acetate. The combined organic layers were washed with brine, driedover MgSO₄ and concentrated to dryness under reduced pressure. Theresultant residue was used directly in the next step without furtherpurification. MS (ESI): 514.2 (M+H⁺).

(2S)-[4-(4-cyano-2-methyl-phenyl)-piperazine-1-carbonyl]-(5S)-[(2-methoxy-acetyl)-methyl-amino]-piperidine-(3S)-carboxylicacid tert-butyl ester was made in an analogous manner.

Part 7

The crude product made above was dissolved in CH₂Cl₂ (1.5 mL) andtreated with TFA (1.5 mL) at rt for 3 h. The mixture was concentrated todryness under reduced pressure to afford piperidine 3-carboxylic acid,which was used directly in the next step without purification. MS (ESI):458.1 (M+H⁺).

Part 8

A solution of the above crude piperidine 3-carboxylic acid, hydroxyamineHCl salt (29 mg, 0.42 mmol) and BOP (111 mg, 0.25 mmol) in DMF (0.42 mL)was treated with diisopropylethylamine (0.11 mL, 0.63 mmol) at rt, undernitrogen, for 2 h. The reaction mixture was applied directly on RP-HPLCto provide(2S)-[4-(4-cyano-2-methyl-phenyl)-piperazine-1-carbonyl]-(5R)-[(2-methoxy-acetyl)-methyl-amino]-piperidine-(3S)-carboxylicacid hydroxyamide as a TFA salt (6.8 mg, 6.9% in 3 steps). MS (ESI):473.2 (M+H⁺).

(2S)-[4-(4-cyano-2-methyl-phenyl)-piperazine-1-carbonyl]-(5S)-[(2-methoxy-acetyl)-methyl-amino]-piperidine-(3S)-carboxylicacid hydroxyamide TFA salt was made in analogous manner.

Example 7(2S,3S,5S)-2-{[4-(4-cyano-2-methylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-N-hydroxy-5-{2-[(2-methoxyethyl)amino]-2-oxoethyl}piperidine-3-carboxamideand(2S,3S,5R)-2-{[4-(4-cyano-2-methylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-N-hydroxy-5-{2-[(2-methoxyethyl)amino]-2-oxoethyl}piperidine-3-carboxamide

The two titled compounds were prepared using procedures analogous tothose for Example 2. The two diastereoisomers were separated by RP-HPLC.

Example 8(2S,3S,5S)-2-{[4-(4-cyano-2-methylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-N-hydroxy-5-{2-oxo-2-[(3R)-tetrahydrofuran-3-ylamino]ethyl}piperidine-3-carboxamideand(2S,3S,5R)-2-{[4-(4-cyano-2-methylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-N-hydroxy-5-{2-oxo-2-[(3R)-tetrahydrofuran-3-ylamino]ethyl}piperidine-3-carboxamide

The two titled compounds were prepared using procedures analogous tothose for Example 2. The two diastereoisomers were separated by RP-HPLC.

Example 9Methyl(3R,5S,6S)-5-[(hydroxyamino)carbonyl]-6-{[(3R)-3-phenylpyrrolidin-1-yl]carbonyl}piperidin-3-ylcarbonate andMethyl(3S,5S,6S)-5-[(hydroxyamino)carbonyl]-6-{[(3R)-3-phenylpyrrolidin-1-yl]carbonyl}piperidin-3-ylcarbonate Part 1

A suspension of lithium aluminum hydride in 80 mL of THF was cooled at0° C. and (R)-phenylsuccinic acid solid was added portionwise through aflexible plastic sleeve so as that not to produce too vigorous anevolution of hydrogen. After addition, the reaction was warmed to rt andthen refluxed overnight. The reaction was then cooled again to 0° C. anddiluted with ether (80 mL). The reaction is quenched over a 30 minperiod with water (3.2 mL), aq. 15% NaOH (3.2 mL, over 20 min), andwater (9.6 mL, over 30 min). The solution was stirred for 30 min and thewhite precipitate was filtered. The filter cake was washed with ether(3×) and the filtrates combined, dried with sodium sulfate andconcentrated to dry. The residue was purified on silica gel, elutingwith 0 to 100% EtOAc in hexane, to give 5.45 g (91%) of thecorresponding diol.

To a solution of the diol made above in 100 mL of dry methylene chlorideat −78° C. was added triethylamine followed by MsCl. The mixture wasallowed to warm up to rt gradually and stirred at rt overnight. Thereaction was quenched with aq. Sodium bicarbonate, extracted withmethylene chloride, dried (MgSO₄), evaporated to dry. The crude residuewas used directly in next step without further purification.

The bis-mesylate, benzylamine and triethylamine in 120 mL of dioxanewere refluxed for 12 h. The crude mixture was concentrated in vacuo, andthe residue was dissolved in methylene chloride, washed with 5% HCl,dried. After evaporated to dry, the residue was purified on silica gel,eluting with 5% MeOH in methylene chloride, to give1-benzyl-(3R)-phenylpyrrolidine (6.6 g, 84.8% in 2 step). LCMS (M+H)238.1.

1-Benzyl-(3R)-phenylpyrrolidine (500 mg, 2.11 mmol) was hydrogenated inthe presence of 20% Pd(OH)₂/C in ethanol, under 50 psi of hydrogenovernight. After filtered off the catalyst, the filtration wasevaporated to dry to provide (3R)-phenylpyrrolidine (310 mg, 100%), LCMS(M+H) 148.0.

Part 2

To a solution of 5-oxo-piperidine-(1,2S,3S)-tricarboxylic acid1,2-dibenzyl ester 3-tert-butyl ester (200 mg, 0.43 mmol) in MeOH (7 ml)and CH₂Cl₂ (7 ml) was added NaBH₄ (97 mg, 2.6 mmol) at −78° C. under anitrogen atmosphere. The resulting mixture was stirred at −78° C. for 1h, then quenched with acetone (2 ml) and allowed to gradually warm toambient temperature over 30 min. The volatiles were removed underreduced pressure and the resulting residue was dissolved in ethylacetate (10 ml), washed with brine, and dried over MgSO₄. Purificationby Combiflash (ethyl acetate in hexane:gradient 0 to 30% in 25 min)afforded 152 mg (75.7%) of(5R/S)-hydroxy-piperidine-(1,2S,3S)-tricarboxylic acid 1,2-dibenzylester 3-tert-butyl ester. MS (ESI): 492.2 (M+Na⁺).

Part 3

To a solution of the above made hydroxy-piperidine (200 mg, 0.426 mmol)in CH₂Cl₂ (1.4 ml) was added methyl chloroformate (48.3 mg, 0.51 mmol),followed by Et₃N (43 mg, 0.43 mmol) and DMAP (2.6 mg) at 0° C. Theresulting mixture was stirred overnight and then concentrated in vacuo.The crude product was purified by Combiflash (ethyl acetate inhexane:gradient 0 to 40% in 25 min) to afford 49 mg (21.8%) of(5R/S)-methoxycarbonyloxy-piperidine-(1,2S,3S)-tricarboxylic acid1,2-dibenzyl ester 3-tert-butyl ester. MS (ESI): 550.1 (M+Na⁺).

Part 4

(5R/S)-methoxycarbonyloxy-piperidine-(1,2S,3S)-tricarboxylic acid1,2-dibenzyl ester 3-tert-butyl ester was coupled with(3R)-phenylpyrrolidine made in Part 1, then carried through to generatethe titled two compounds, using procedures analogous to Part 3, 6, 7 andPart 8 in Example 6. The two diastereoisomers were separated by RP-HPLC.MS (ESI): 392.2 (M+H⁺).

Example 10(2S,3S)—N,5-dihydroxy-2-{[(3R)-3-phenylpyrrolidin-1-yl]carbonyl}piperidine-3-carboxamide

The titled compound was prepared using procedures analogous to Part 3 inthose of Example 9 as an inseparable mixture of diastereoisomers at C-5on the piperidine ring (2.4 mg). MS (ESI): 334.2 (M+H⁺).

Example 11(5S,6S)-5-[(hydroxyamino)carbonyl]-6-{[(3R)-3-phenylpyrrolidin-1-yl]carbonyl}piperidin-3-ylmethylcarbamate Part 1

To a solution of (5R/S)-hydroxy-piperidine-(1,2S,3S)-tricarboxylic acid1,2-dibenzyl ester 3-tert-butyl ester (200 mg, 0.426 mmol) in CH₂Cl₂(1.4 ml) was added methyl isocyanate (29 mg, 0.51 mmol), followed byEt₃N (43 mg, 0.43 mmol) at 0° C. The resulting mixture was stirred at rtovernight and then concentrated in vacuo. The crude product was purifiedby Combiflash (ethyl acetate in hexane:gradient 0 to 40% in 25 min) toafford 44 mg (19.6%) of(5R/S)-methylcarbamoyloxy-piperidine-(1,2S,3S)-tricarboxylic acid1,2-dibenzyl ester 3-tert-butyl ester.

Part 2

The titled compound was prepared using procedures analogous to Part 3 inExample 9 as an inseperable diastereo isomer mixtures at piperidine5-position (6.7 mg). MS (ESI): 391.2 (M+H⁺).

Example 12tetrahydro-2H-pyran-4-yl(3R,4S)-3-[(hydroxyamino)carbonyl]-4-{[(3R)-3-phenylpyrrolidin-1-yl]carbonyl}piperidine-1-carboxylate

(1a) To a stirred solution of N-benzyloxycarbonyl-β-alanine (11.16 g,50.00 mmol) in anhydrous THF (160 mL) and DMF (40 mL) at 0° C. wasslowly added NaH (60% in oil, 6.000 g, 150.0 mmol). After stirring at 0°C. for 15 min, benzyl bromide (9.10 mL, 75.00 mmol) was added. Thereaction mixture was stirred at rt for 22 h. It was quenched with water(90 mL), followed by 1 N HCl (110 mL), and extracted three times withethyl acetate. The combined organic layers were washed with brine, driedover MgSO₄, filtered and concentrated under reduced pressure. Theresidue was purified by Combiflash (40-60% EtOAc/hexane) to afford3-{benzyl[(benzyloxy)cabonyl]amino}propanoic acid as a viscous paleyellow oil (14.2 g, 91% in yield). MS (ESI): 312.0 (M−H).

(1b) To a stirred solution of3-{benzyl[(benzyloxy)cabonyl]amino}propanoic acid (13.80 g, 44.04 mmol)and triethylamine (18.5 mL, 132.1 mmol) in anhydrous THF (220 mL) at−25° C. was slowly added pivaloyl chloride (6.03 mL, 48.44 mmol) toimmediately form a white precipitate. The reaction mixture was stirredat −20° C. for 1 h, prior to the sequential addition of LiCl and(R)-(+)-4-benzyl-2-oxazolidinone. After stirring the reaction mixture atrt for 16 h, the reaction was quenched with saturated aqueous NaHCO₃ (80mL) and water (80 mL). The aqueous phase was extracted twice with ethylacetate and the combined organic layers were washed with brine, driedover MgSO₄, filtered and concentrated under reduced pressure. Theresidue was purified by Combiflash (20-40% EtOAc/hexane) to givebenzyl-{3-[(4R)-benzyl-2-oxo-1,3-oxazolidin-3-yl)-3-oxo-propyl]-carbamicacid phenyl ester as a colorless semi-solid (17.00 g, 82% in yield). MS(ESI): 473.1 (M+H⁺).

(1c) To a stirred solution of diisopropylamine (5.96 mL, 42.16 mmol) inanhydrous THF (70 mL) at −78° C. was added n-butyllithium (1.6 M inHexane, 26.4 mL, 42.16 mmol). After stirring at 0° C. for 30 min, theLDA was added To a solution ofbenzyl-{3-[(4R)-benzyl-2-oxo-1,3-oxazolidin-3-yl)-3-oxo-propyl]-carbamicacid phenyl ester (16.60 g, 35.13 mmol) in anhydrous THF (70 mL) at −78°C. via cannula. After stirring at −78° C. for 1 h, tert-butylbromoacetate (6.35 mL, 42.16 mmol) was added. The reaction mixture wasslowly warmed to 30° C. over 1 h, and stirred at −30° C. for 4 h. It wasquenched with water (70 mL) and saturated aqueous ammonium chloride (70mL) and extracted twice with ethyl acetate. The combined organic layerswere washed with brine, dried over MgSO₄, filtered and concentratedunder reduced pressure. The residue was purified by Combiflash (15-35%EtOAc/hexane) to provide 7.547 g (37%) oftert-butyl(3R)-({benzyl[(benzyloxy)carbonyl]amino}methyl)-4-[(4R)-benzyl-2-oxo-1,3-oxazolidin-3-yl]-4-oxo-butanoate.MS (ESI): 609.2 (M+Na⁺).

(1d) To a solution oftert-butyl(3R)-({benzyl[(benzyloxy)carbonyl]amino}methyl)-4-[(4R)-benzyl-2-oxo-1,3-oxazolidin-3-yl]-4-oxo-butanoate(6.703 g, 11.43 mmol) in THF (57 mL) and water (37 mL) at 0° C. wasadded 30% hydrogen peroxide (4.67 mL, 45.72 mmol). After 5 min at 0° C.,a solution of LiOH (559 mg, 22.86 mmol) in water (20 mL) was added andthe reaction mixture was stirred at 0° C. for 1.5 h. and then at rt for1 h. The reaction was quenched with 10% sodium thiosulfate (70 mL),acidified with 1 N HCl (30 mL) to pH 3, and extracted three times withethyl acetate. The combined organic layers were washed with brine, driedover MgSO₄, filtered and concentrated under reduced pressure. Theresidue was purified by Combiflash (30-60% EtOAc/hexane) to provide4.642 g (95%) of(2R)-({benzyl[(benzyloxy)cabonyl]amino}methyl)-4-tert-butoxy-4-oxobutanoicacid. MS (ESI): 426.2 (M−H⁺).

(1e) To a stirred solution of diisopropylamine (3.67 mL, 26.06 mmol) inanhydrous THF (27 mL) at −78° C. was added n-butyllithium (1.6 M inhexane, 16.3 mL, 26.06 mmol). After stirring at 0° C. for 30 min, it wasadded To a solution of(2R)-({benzyl[(benzyloxy)cabonyl]amino}methyl-4-tert-butoxy-4-oxobutanoicacid (4.642 g, 10.86 mmol) in anhydrous THF (27 mL) at −78° C. viacannula. After stirring at −78° C. for 1 h, allyl iodide (1.32 mL, 14.12mmol) was added and the reaction mixture was slowly warmed to 30° C.over 3.5 h and stirred at −30° C. for 2.5 h. The reaction was quenchedwith water (50 mL) and 1 N HCl (50 mL), extracted three times with ethylacetate. The combined organic layers were washed with brine, dried overMgSO₄, filtered and concentrated under reduced pressure. The residue waspurified by Combiflash (20-60% EtOAc/hexane) to afford 3.256 g (64%) of(2R,3S)-2-({benzyl[(benzyloxy)cabonyl]amino}methyl)-4-(tert-butoxycarbonyl)-5-hexenoicacid. MS (ESI): 466.2 (M−H⁺).

(1f) To a stirred solution of(2R,3S)-2-({benzyl[(benzyloxy)cabonyl]amino}methyl)-4-(tert-butoxycarbonyl)-5-hexenoicacid (2.930 g, 6.267 mmol) in anhydrous acetonitrile (15 mL) at rt wasadded DBU (1.91 mL, 12.53 mmol), followed by methyl iodide (0.98 mL,15.67 mmol). After stirring at rt for 3 h, the reaction was quenchedwith water (60 mL) and extracted twice with ethyl acetate. The combinedorganic layers were washed with brine, dried over MgSO₄, filtered andconcentrated under reduced pressure. The residue was purified byCombiflash (10-20% EtOAc/hexane) to provide 2.523 g (84%) 4-methyl1-tert-butyl(2S,3R)-2-allyl-3-({benzyl[(benzyloxy)cabonyl]amino}methyl)butanedioateas a colorless viscous oil (.MS (ESI): 504.2 (M+Na⁺).

(1g) To a stirred solution of 4-methyl1-tert-butyl(2S,3R)-2-allyl-3-({benzyl[(benzyloxy)cabonyl]amino}methyl)butanedioate(2.336 g, 4.851 mmol) in dichloromethane (97 mL) at −78° C. was bubbledozone. After the solution turned blue, ozone bubbling continued foradditional 15 min. Nitrogen was then bubbled into the mixture until theblue color disappeared. The reaction was quenched with dimethyl sulfide(1.78 mL, 24.26 mmol) and the solution was stirred at rt for 2 h. Thesolvent was removed under reduced pressure and the residue was purifiedby Combiflash (15-25% EtOAc/hexane) to provide 1.853 g (79%) of 1-methyl4-tert-butyl(2R,3S)-2-({benzyl[(benzyloxy)cabonyl]amino}methyl)-3-(2-oxoethyl)butanedioateas a colorless viscous oil (1.853 g, 79% in yield). MS (ESI): 506.1(M+Na⁺).

(1h) To a solution of 1-methyl4-tert-butyl(2R,3S)-2-({benzyl[(benzyloxy)cabonyl]amino}methyl)-3-(2-oxoethyl)butanedioate (836 mg, 1.729 mmol) inmethanol (17 mL) was added 10% palladium on carbon (251 mg). Thereaction mixture was stirred under 55 psi hydrogen at rt for 15.5 h. Thereaction mixture was diluted with methanol, filtered through a pad ofCelite and washed with methanol. The filtrate was concentrated underreduced pressure to provide 417 mg (99%) ofpiperidine-(3R,4S)-3,4-dicarboxylic acid 4-tert-butyl ester 3-methylester. MS (ESI): 244.2 (M+H⁺).

(1i) To a stirred solution of piperidine-(3R,4S)-3,4-dicarboxylic acid4-tert-butyl ester 3-methyl ester (415 mg, 1.706 mmol) in anhydrousdichloromethane (11 mL) at rt was added 4-methylmorpholine (0.474 mL,4.265 mmol) and N-(benzyloxycarbonyloxy) succinimide (651 mg, 2.559mmol). After stirring the reaction mixture at rt for 25 h, the reactionwas quenched with saturated aqueous NaHCO₃ (30 mL) and extracted twicewith ethyl acetate. The combined organic layers were washed with brine,dried over MgSO₄, filtered and concentrated under reduced pressure. Theresidue was purified by Combiflash (15-25% EtOAc/hexane) to afford 490mg (76%) of piperidine-(3R,4S)-1,3,4-tricarboxylic acid 1-benzyl ester4-tert-butyl ester 3-methyl ester as a colorless solid. MS (ESI): 400.0(M+Na⁺).

(1j) To a stirred solution of piperidine-(3R,4S)-1,3,4-tricarboxylicacid 1-benzyl ester 4-tert-butyl ester 3-methyl ester (465 mg, 1.232mmol) in dichloromethane (12 mL) at rt was added trifluoroacetic acid(12 mL) and water (0.6 mL). The reaction mixture was stirred at rt for 5h. The reaction mixture was concentrated under reduced pressure and theresidue was azeotropically washed with toluene (3+) to provide 396 mg(100%) of piperidine-(3R,4S)-1,3,4-tricarboxylic acid 1-benzyl ester3-methyl ester. MS (ESI): 320.1 (M−H⁺).

(1k) To a stirred solution of piperidine-(3R,4S)-1,3,4-tricarboxylicacid 1-benzyl ester 3-methyl ester (208 mg, 0.647 mmol) in anhydrous DMF(6 mL) at rt was added (3R)-3-phenyl-pyrrolidine hydrochloride (178 mg,0.971 mmol), PyBOP (382 mg, 0.712 mmol), followed by diisopropylethylamine (0.566 mL, 3.235 mmol). After stirring the reaction mixture at rtovernight, the reaction was quenched with saturated aqueous NaHCO₃ (20mL) and extracted twice with ethyl acetate. The combined organic layerswere washed with brine, dried over MgSO₄, filtered and concentratedunder reduced pressure. The residue was purified by Combiflash (40-60%EtOAc/hexane) to provide 200 mg (69%) of(4S)-[(3R)-3-phenyl-pyrrolidine-1-carbonyl]-piperidine-(3R)-1,3-dicarboxylicacid 1-benzyl ester 3-methyl ester MS (ESI): 451.1 (M+H⁺).

(1l) To a solution of(4S)-[(3R)-3-phenyl-pyrrolidine-1-carbonyl]-piperidine-(3R)-1,3-dicarboxylicacid 1-benzyl ester 3-methyl ester (143 mg, 0.317 mmol) in methanol (8mL) was added 10% palladium on carbon (29 mg). The reaction mixture wasstirred under 1 atm hydrogen balloon at rt for 21 h. Upon completion thereaction mixture was diluted with methanol, filtered through a pad ofCelite and washed with methanol. The filtrate was concentrated underreduced pressure to afford 100 mg (100%)(4S)-[(3R)-3-phenyl-pyrrolidine-1-carbonyl]-piperidine-(3R)-carboxylicacid 3-methyl ester. MS (ESI): 317.2 (M+H⁺)

(1m) To a stirred solution of(4S)-[(3R)-phenyl-pyrrolidine-1-carbonyl]-piperidine-(3R)-carboxylicacid 3-methyl ester (23 mg, 0.0727 mmol) in anhydrous dichloromethane (2mL) at rt was added diisopropylethyl amine (0.038 mL, 0.218 mmol) andcarbonic acid 4-nitro-phenyl ester tetrahydro-pyran-4-yl ester (29 mg,0.109 mmol, prepared using procedure analogous to example 34, step 1).The reaction mixture was stirred at rt for 22 h and then purifieddirectly by Combiflash (60-90% EtOAc/hexane) to afford 27 mg (84%) of(4S)-[(3R)-phenyl-pyrrolidine-1-carbonyl]-piperidine-(3R)-1,3-dicarboxylicacid 3-methyl ester 1-(tetrahydro-pyran-4-yl) ester MS (ESI): 445.1(M+H⁺).

(1n) Preparation of NH₂OH/NaOMe (1.5 M in MeOH): To a stirred solutionof hydroxylamine hydrochloride (702 mg, 10.00 mmol) in anhydrousmethanol (3 mL) at rt was added NaOMe (25 wt % in MeOH, 3.43 mL, 15.00mmol). The reaction mixture was heated at 55° C. for 5 min and thenallowed to gradually warm to rt before cooling to 0° C. Filtration ofthe crude mixture afforded a clear solution assumed to be a ca. 1.5 Msolution of NH₂OH/NaOMe in MeOH.

To a stirred solution of(4S)-[(3R)-phenyl-pyrrolidine-1-carbonyl]-piperidine-(3R)-1,3-dicarboxylicacid 3-methyl ester 1-(tetrahydro-pyran-4-yl) ester (24 mg, 0.054 mmol)in anhydrous methanol (1.5 mL) at rt was added the above NH₂OH/NaOMe(1.5 M in MeOH, 0.72 mL, 1.08 mmol). After stirring the reaction mixtureat rt for 16 h, the reaction was quenched with 1 N HCl (1 mL) andsaturated aqueous ammonium chloride (10 mL) and extracted twice withethyl acetate. The combined organic layers were washed with brine, driedover NaSO₄, filtered and concentrated under reduced pressure. Theresidue was purified by reverse phase HPLC (eluting with 5-95%acetonitrile/water (0.05% TFA)) to afford 6.8 mg (28%) of(3R)-hydroxycarbamoyl-4-[(3R)-phenyl-pyrrolidine-1-carbonyl)]-piperidine-1-carboxylicacid tetrahydro-pyran-4-yl ester as a colorless semi-solid. MS (ESI):446.1 (M+H⁺).

Example 13(3R)-tetrahydrofuran-3-yl(3R,4S)-3-[(hydroxyamino)carbonyl]-4-{[(3R)-3-phenylpyrrolidin-1-yl]carbonyl}piperidine-1-carboxylate

The titled compound was prepared using procedures analogous to those inExample 12. ESI MS: m/z 432.1 (M+H)⁺.

Example 14(3S)-tetrahydrofuran-3-yl(3R,4S)-3-[(hydroxyamino)carbonyl]-4-{[(3R)-3-phenylpyrrolidin-1-yl]carbonyl}piperidine-1-carboxylate

The titled compound was prepared using procedures analogous to those inExample 12. ESI MS: m/z 432.1 (M+H)⁺.

Example 152-methoxyethyl(3R,4S)-3-[(hydroxyamino)carbonyl]-4-{[(3R)-3-phenylpyrrolidin-1-yl]carbonyl}piperidine-1-carboxylate

The titled compound was prepared using procedures analogous to those inExample 12. ESI MS: m/z 420.1 (M+H)⁺.

Example 16tetrahydro-2H-pyran-4-yl(3R,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1-carboxylate

The titled compound was prepared using procedures analogous to those inExample 12. ESI MS: m/z 461.1 (M+H)⁺.

Example 17(3R)-tetrahydrofuran-3-yl(3R,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1-carboxylate

The titled compound was prepared using procedures analogous to those inExample 12. ESI MS: m/z 447.1 (M+H)⁺.

Example 18(3S)-tetrahydrofuran-3-yl(3R,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1-carboxylate

The titled compound was prepared using procedures analogous to those inExample 12. ESI MS: m/z 447.2 (M+H)⁺.

Example 192-methoxyethyl(3R,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1-carboxylate

The titled compound was prepared using procedures analogous to those inExample 12. ESI MS: m/z 435.1 (M+H)⁺.

Example 20tetrahydro-2H-pyran-4-yl(3R,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenylpiperidin-1-yl)carbonyl]piperidine-1-carboxylate

The titled compound was prepared using procedures analogous to those inExample 12. ESI MS: m/z 460.2 (M+H)⁺.

Example 21(3R)-tetrahydrofuran-3-yl(3R,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenylpiperidin-1-yl)carbonyl]piperidine-1-carboxylate

The titled compound was prepared using procedures analogous to those inExample 12. ESI MS: m/z 446.2 (M+H)⁺.

Example 22(3S)-tetrahydrofuran-3-yl(3R,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenylpiperidin-1-yl)carbonyl]piperidine-1-carboxylate

The titled compound was prepared using procedures analogous to those inExample 12. ESI MS: m/z 446.2 (M+H)⁺.

Example 232-methoxyethyl(3R,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenylpiperidin-1-yl)carbonyl]piperidine-1-carboxylate

The titled compound was prepared using procedures analogous to those inExample 12. ESI MS: m/z 444.2 (M+H)⁺.

Example 24 (1S,2S,4S)— N,4-dihydroxy-2-{[(3R)-3-phenylpyrrolidin-1-yl]carbonyl}cyclohexanecarboxamide Part 1

Starting material 3a,4,7,7a-tetrahydro-isobenzofuran-1,3-dione (30.4 g,0.2 mole) was suspended in methanol (40 mL) and the mixture was stirredat room temperature overnight to form a homogenous mixture. The reactionmixture was cooled to 0° C. and thionyl chloride (14.6 ml) was addeddropwise. After completion of the addition, the cold bath was removedand the mixture was stirred at room temperature for 3 hours. Thevolatiles were then removed in-vacuo and the resulting residue wasneutralized with saturated sodium bicarbonate solution. The product wasextracted with ethyl acetate (×3) and the combined extracts were washedwith water (×1), brine (×1), dried over MgSO₄, filtered and concentratedunder reduced pressure. The resulting residue was purified bydistillation to obtain 37.06 g (93%) of pure product.

Part 2

To a solution of diester from Part 1 (37 g, 187 mmole) in acetone (127ml) was added a solution of LE (25 mg, 1025 units, 41 unit/mg) in apremade phosphate buffer solution (4 ml) (Phosphate buffer solution (pH8.0) was prepared by adding KH₂PO₄ (34.43 g, 252 mmole) and NaOH (9.30g, 233 mmole) to distilled water (2530 ml)) The homogenous reactionmixture was gently stirred at rt, while maintaining a pH between 7 and 8by the occasional addition of aqueous NaOH. After 8 days, the solutionwas saturated with NaCl and acidified to pH 3.0 with a solution of HCl.The mixture was extracted with EtOAc (600 ml×3) and the combinedextracts were washed with water (×1), brine (×1), dried over MgSO4,filtered, and concentrated in-vacuo to afford the desired product.

Part 3

A mixture of optically pure mono acid made above (25 g), 2-methylpropene (100 ml), concentrated H₂SO₄ (1.63 ml) in methylene chloride (40ml) in a sealed reaction vessel was stirred at room temperature for 3days. The mixture was poured into saturated sodium bicarbonate solution,and extracted with hexane-diethyl ether (×2). The combined extracts werewashed with water (×1), brine (×1), dried over MgSO₄, filtered andconcentrated under reduced pressure to afford 30.3 g (91%) of thedesired product as an oil.

Part 4

The tert-butyl ester made above was dissolved in methanol (82 ml) andcooled to 0° C., before slowly adding 2 N NaOH (NaOH, 13.12 g indistilled water 164 ml). After stirring the reaction mixture at rt for 2d, the mixture was acidified with 1 N HCl solution, extracted with EtOAc(×3). The combined extracts were washed with water (×1), brine (×1),dried over MgSO₄, filtered and concentrated in-vacuo to afford thedesired product in quantitative yield.

Part 5

To a 0° C. solution of KOBu-t (10.61 mL, 1.0 M KOBu-t THF and 6.1 mL ofTHF) was added slowly cyclohex-4-ene-(1R,2S)-dicarboxylicacid-tert-butyl ester (1.6 g, 7.07 mmole) in THF (12.2 ml). The reactionmixture was stirred at 0° C. for 10 to 15 min and then at rt for 1 to 2hours. After the reaction was complete, 1 N HCl was carefully addeduntil the pH was ca. 2 and the product was extracted with EtOAc (×2).The combined extracts were washed with water (×1), brine (×1), driedover MgSO₄, filtered and concentrated under reduced pressure. Theresulting residue was purified by flash column to afford 1.56 g (97%) ofthe desired product.

Part 6

To a solution of the epimerized compound from Part 5_(5.5 g, 24.3 mmol)dissolved in methylene chloride (60 ml) was added I₂ (18.5 g, 72.9mmol), KI (24.2 g, 145.6 mmol), and NaHCO₃ (6.1 g, 72.9 mmol)successively, followed by distilled water (90 mL). The mixture wasstirred in the absence of light at rt for 2 days. At this time saturatedNa₂S₂O₃ solution was added and the product was extracted with methylenechloride. The extract was washed with water (×1), brine (×1), dried overMgSO₄, filtered and concentrated under reduced pressure. The crudematerial was purified by flash column to afford 6.21 g (82%) of thedesired product.

Part 7

To a solution of iodo compound made above (6.6 g, 18.7 mmol) in toluene(55 mL) was added tris(trimethylsilyl)silane (6.94 mL, 22.5 mmol),followed by AIBN (0.31 g, 1.87 mmol). The mixture was heated at 90° C.for 1.5 hours. After cooling, the reaction mixture to ambienttemperature the reaction was quenched with 10% citric acid and extractedwith EtOAc. The organic phase was washed with water (×1), saturatedNaHCO₃ solution (×1), water (×1), brine (×1), dried over MgSO₄, andconcentrated in-vacuo. The residue was purified by flash column toafford 3.42 g (80%) of the desired product.

Part 8

A solution (R)-3-phenylpyrrolidine (234 mg, 1.59 mmol) and 2 M AlMe₃ intoluene (0.86 mL) was stirred at rt for 30 min. To the solution wasadded the lactone compound (300 mg, 1.33 mmol) in THF (0.5 ml). Themixture was stirred at 40° C. overnight. After cooling to rt, thereaction mixture was extracted with EtOAc. The organic layers werewashed with 10% citric acid (×1), water (×1), brine (×1), dried overMgSO₄, filtered, and concentrated under reduced pressure. The resultingcrude product was purified by flash chromatography to afford 180 mg(36%) of desired product.

Part 9

The compound made above was stirred in methylene chloride-TFA-H₂O(45:50:5) for 3 hours. After the reaction was complete according to HPLCanalysis, the volatiles were removed in-vacuo to afford the desiredproduct in quantitative yield.

Part 10

A solution of compound from Part 9 (12 mg, 0.038 mmol), NH₂OH.HCl (7.9mg, 0.113 mmol), BOP (17.6 mg, 0.039 mmol) and DIEA (22.1 mg, 0.17 mmol)in DMF (0.4 mL) was stirred at room temperature for 3 hours. The crudereaction mixture was directly purified by preparative HPLC To afford 4mg (32%) of desired product was obtained. MS m/z: 333.1 (M+H⁺); 687.3(2×M+Na⁺).

Example 25(1S,2S,5S)—N,5-dihydroxy-2-{[4-phenyl-3,6-dihydropyridin-1(2H)-yl]carbonyl}cyclohexanecarboxamidePart 1

The mixture of 7-oxo-6-oxa-bicyclo[3.2.1]octane-2-carboxylic acidtert-butyl ester from Experiment 24, Part 7 (0.92 g, 4.07 mmol) inmethylene chloride (3 ml) and TFA (3 mL) was stirred a room temperaturefor 1.5 hours. After the reaction was complete according to TLC analysisthe volatiles were removed in-vacuo to afford 0.67 (97%) of the desiredproduct.

Part 2

To a 0° C. solution of the acid made above (30 mg, 0.176 mmol) in DMF(0.4 mL) was added 4-phenyl-1,2,5,6-tetrahydropyridine (41 mg, 0.212mmol) and BOP (82 mg, 0.185 mmol). After stirring for 5 minDIEA (69 mg,0.529 mmol) was added And the mixture was allowed to gradually warm toambient temperature and stirred overnight. The reaction was quenchedwith saturated sodium bicarbonate solution and extracted with EtOAc(×3). The combined extracts were washed with water (×1), brine (×1),dried over MgSO₄, filtered and concentrated under reduced pressure toprovide the product in quantitative yield.

Part 3

A solution of compound made from Part 2 and LiOH H₂O (22 mg, 0.529 mmol)in THF (0.5 mL) and H₂O (0.1 mL) was stirred at rt for 2 h. After theTLC indicated that the start material was completely consumed, 1 N HClwas carefully added until the pH was ca. 2. The reaction mixture wasextracted with EtOAc (×3) and the combined extracts were washed withwater (×1), brine (×1), dried over MgSO₄ filtered, and concentratedunder reduced pressure to provide the desired5-hydroxy-2-(-phenyl-3,6-dihydro-2H-pyridine-1-carbonyl)-cyclohexanecarboxylicacid.

Part 4

To a solution of the compound made above (24 mg, 0.07 mmol) and NH₂OHH₂O in DMF (0.4 ml) was added BOP (34 mg, 0.077 mmol). After stirringfor 5 min, DIEA (33 mg, 0.255 mmol) was added. The mixture was stirredat rt for 3 h. After HPLC analysis indicated that the starting materialwas completely consumed the crude reaction mixture was purified bypreparative HPLC to afford 16 mg (63%) of the desired product. MS m/z345.1 (M+H⁺); 367.1 (M+Na⁺); 711.2 (2×M+Na⁺).

Example 26(1S,2S,5S)—N,5-dihydroxy-2-[(4-phenylpiperidin-1-yl)carbonyl]cyclohexanecarboxamide

To a solution of(5S)-hydroxy-(2S)-(4-phenyl-3,6-dihydro-2H-pyridine-1-carbonyl)-cyclohexane-(1S)-carboxylicacid hydroxyamide (5 mg) in methanol (1 mL) was added 5% Pd on BaSO₄.The mixture was stirred under hydrogen 1 atm at room temperature for 2h. Upon completion of the reaction, the reaction mixture was filteredthrough a pad of celite and the filtrate was concentrated to afford 2.5mg (50%) of the desired product. MS m/z 347.1 (M+H⁺); 369.1 (M+Na⁺);715.3 (2×M+Na⁺)⁺.

Example 27(1S,2S,5S)—N,5-dihydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxamide

The titled compound was prepared using procedures analogous to those inExample 25.

Example 28(1S,2S,5S)—N,5-dihydroxy-2-[(3-phenyl-2,5-dihydro-1H-pyrrol-1-yl)carbonyl]cyclohexanecarboxamidePart 1. tert-butyl 3-hydroxy-3-phenylpyrrolidine-1-carboxylate

To a solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (1 g, 5.40mmol) in ether (20 ml) was added dropwise phenylmagnesium bromide (10.3mL, 3.0 M in ether, 6.21 mmol) at rt under nitrogen. The reaction washeated to reflux for 15 min, then cooled to rt, poured into sat. NH4Cl,extracted with ether (3×). The combined organic layers were dried overNa₂SO₄, concentrated in vacuo. The crude residue was purified by flashcolumn chromatography to yield the desired product (700 mg, 49.24%).LCMS (M+H) 264.160.

Part 2. 3-phenyl-2,5-dihydro-1H-pyrrole

A mixture of tert-butyl 3-hydroxy-3-phenylpyrrolidine-1-carboxylate(0.36 g, 0.0014 mol) and trifluoroacetic acid (2.0 mL, 0.026 mol) wasstirred under nitrogen at room temp for 1 h. The volatile was removedunder vacuum and evaporated with toluene twice. The residue was used innext step w/o further purification. LCMS: 146.1 (M+H)⁺.

Part 3

The titled compound was then prepared using procedures analogous tothose in Example 25.

Example 29(1S,2S)—N-hydroxy-2-{[(3R)-3-phenylpyrrolidin-1-yl]carbonyl}-5-pyrrolidin-1-ylcyclohexanecarboxamideStep 1: Preparation of 2-(3-Phenyl-pyrrolidine-1-carbonyl)-6-oxabicyclo[3.2.1]octan-7-one

To a solution of 7-oxo-6-oxa-bicyclo[3.2.1]octane-2-carboxylic acidtert-butyl ester (500 mg) in methylene chloride (3 mL was added TFA (3mL). After stirring the mixture at rt for 2 h, the solution wasconcentrated under reduced pressure. The residue was azeotropicallywashed with methylene chloride (×3) and redissolved in DMF (3 mL). Tothis solution was added (R)-3-phenylpyrrolidine and the resultantmixture was cooled to 0° C., prior to the sequential addition of PyBOP(1.25 g) and diisopropylethylamine (0.42 ml). After stirring the mixtureat rt overnight, the reaction solution was diluted with EtOAc and washedwith saturated NaHCO₃ aqueous solution (×3), water, and brine. Theorganic phase was dried over MgSO₄, filtered and concentrated underreduced pressure. The residue was purified by flash chromatography(eluting with 8% methanol in methylene chloride). MS (ESI): 300.1 (M+H⁺)

Step 2: Preparation of5-Hydroxy-2-(3-phenyl-pyrrolidine-1-carbonyl)-cyclohexanecarboxylic acidbenzyl ester

To a solution of the compound made above (400 mg) in THF (4 mL) wasadded lithium hydroxide (302 mg), followed by water (1 mL). After 3 h,the reaction mixture was diluted with 1N HCl and extracted with EtOAc(3×30 mL). The organic phases were washed with brine, dried over MgSO₄,filtered, and concentrated under reduced pressure. The residue was usedwithout further purification in the following step.

To a solution of the above residue in acetonitrile (10 mL) was addedbenzyl bromide (0.41 mL), followed by DBU (0.51 mL). After stirring thereaction mixture at rt overnight the reaction mixture was concentratedunder reduced pressure and then the residue was dissolved in EtOAc,followed by washing with 10% citric acid aqueous solution and brine. Theorganic phases were dried over MgSO₄, filtered, and concentrated underreduced pressure. The residue was purified by flash chromatography(eluting with 5% methanol in methylene chloride). MS (ESI): 408.2 (M+H⁺)

Step 3: Preparation of5-oxo-2-(3-phenyl-pyrrolidine-1-carbonyl)-cyclohexanecarboxylic acidbenzyl ester

To a solution of alcohol compound from Step 2 (400 mg) was addedDess-Martin reagent (500 mg) and the mixture was stirred at rt for 3 h.After the reaction was complete the mixture was diluted with methylenechloride followed by the addition of 0.1 N NaOH aqueous solution (12 mL)and the stirring was continued for about 20 min. The organic phases werewashed with 0.1 N NaOH solution, brine, dried over MgSO₄, andconcentrated under reduced pressure. The residue was purified by flashchromatographed (eluting with 5% methanol in methylene chloride). MS(ESI): 406.1 (M+H⁺)

Step 4: Preparation of2-(3-Phenyl-pyrrolidine-1-carbonyl)-5-pyrrolidin-1-yl-cyclohexanecarboxylicacid benzyl ester

To a solution of the ketone compound made above (30 mg) in1,2-dichloroethane was added pyrrolidine (6 μL). The mixture was stirredat rt about 10 min, prior to the addition of NaBH(OAc)₃ (24 mg). Theresultant mixture was stirred for an additional hour and then dilutedwith EtOAc and washed with saturated NaHCO₃, and brine. The organicphases were dried over MgSO₄, filtered and concentrated to dry underreduced pressure. MS (ESI): 461.2 (M+H⁺)

Step 5: Preparation of2-(3-Phenyl-pyrrolidine-1-carbonyl)-5-pyrrolidin-1-yl-cyclohexanecarboxylicacid hydroxyamide

To a solution of the above made compound (30 mg, crude) in methanol (1mL) was added palladium on carbon (20 mg). The suspension was stirredunder hydrogen balloon overnight. The mixture was filter through a padof celite and concentrated in-vacuo. The residue was used in the nextstep without further purification. MS (ESI): 371.2 (M+H⁺).

To a solution of the above residue in DMF (0.3 mL) was addedhydroxylamine (14 mg) and the mixture was cooled to 0° C., prior to thesequential addition of PyBOP (34 mg) and NMM (18 μL). The mixture wasstirred at rt for about 3 h and then applied directly on preparativeHPLC to afford the final product. MS (ESI): 386.2 (M+H⁺)

Example 30(1S,2S,5S)—N-hydroxy-2-{[(3R)-3-phenylpyrrolidin-1-yl]carbonyl}-5-morpholin-4-ylcyclohexanecarboxamide

This compound was prepared using procedures analogous to those forExample 29. MS (ESI): 402.2 (M+H⁺)

Example 31(1S,2S,5R)—N-hydroxy-2-{[(3R)-3-phenylpyrrolidin-1-yl]carbonyl}-5-morpholin-4-ylcyclohexanecarboxamide

This compound was prepared using procedures analogous to those forExample 29. MS (ESI): 402.2 (M+H⁺)

Example 32(1S,2S)—N-hydroxy-5-[(3R)-3-hydroxypyrrolidin-1-yl]-2-{[(3R)-3-phenylpyrrolidin-1-yl]carbonyl}cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forExample 29. MS (ESI): 402.2 (M+H⁺)

Example 33(1S,2S,5S)-2-{[4-(4-tert-butylphenyl)piperazin-1-yl]carbonyl}-N,5-dihydroxycyclohexanecarboxamideStep 1: Preparation of2-[4-(4-tert-Butyl-phenyl)-piperazine-1-carbonyl]-6-oxa-bicyclo[3.2.1]octan-7-one

This compound was prepared using procedures analogous to Example 29,Step 1. MS (ESI): 371.1 (M+H⁺)

Step 2: preparation of2-[4-(4-tert-Butyl-phenyl)-piperazine-1-carbonyl]-5-hydroxy-cyclohexanecarboxylicacid hydroxyamide

To a solution of the above made compound (130 mg) in THF (2 mL) wasadded lithium hydroxide (45 mg), followed by water (0.5 mL). Afterstirring at rt for 3 h, the reaction mixture was diluted with 1N HClsolution and extracted with EtOAc (3×15 mL). The organic phases werewashed with brine, dried over MgSO₄, and concentrated to dry underreduced pressure. The residue was used in next step without furtherpurification.

The crude residue (45 mg) was dissolved in DMF (0.3 mL), andhydroxylamine HCl salt (25 mg) was added. The mixture was cooled to 0°C. and PyBOP (68 mg) was added, followed by DIEA (93 μL). After stirringthe reaction mixture at rt for 3 h, the crude reaction mixture wasapplied directly on preparative HPLC to afford the final product. MS(ESI): 404.2 (M+H⁺)

Example 34(3S)-tetrahydrofuran-3-yl((3S,4S)-3-[(hydroxyamino)carbonyl]-4-{[(3R)-3-phenylpyrrolidin-1-yl]carbonyl}cyclohexyl)methylcarbamateStep 1: Preparation of Carbonic acid 4-nitro-phenyl estertetrahydro-furan-3-yl ester

To a solution of p-nitrophenyl chloroformate (1.21 g) in methylenechloride at 0° C. was added S-(+)-3-hydoxytetrahydrofuran (0.51 g),followed by NMM (0.66 mL). After stirring the mixture at rt for 2 h thevolatiles were removed under reduced pressure and the resulting residuewas dissolved in a small amount of methylene chloride and filtered. Thefiltrate was concentrated under reduced pressure and subjected to flashchromatography (eluting with 30% ethyl acetate in methylene chloride) toafford the titled compound.

Step 2: Preparation of5-Methylamino-2-(3-phenyl-pyrrolidine-1-carbonyl)-cyclohexanecarboxylicacid benzyl ester

This compound was prepared using procedures analogous to Step 4 inExample 29. MS (ESI): 421.2 (M+H⁺)

Step 3: Preparation of5-[Methyl-(tetrahydro-furan-3-yloxycarbonyl)-amino]-2-(3-phenyl-pyrrolidine-1-carbonyl)-cyclohexanecarboxylicacid benzyl ester

To a solution of the compound made above (37 mg) in THF (0.3 mL) wasadded DIEA (31 μL), followed by carbonic acid 4-nitro-phenyl estertetrahydro-furan-3-yl ester (25 mg) in THF (0.3 mL). After stirring themixture at rt for 24 hours, the volatiles were removed under reducedpressure. The residue was purified by flash chromatography (eluting with5% methanol in methylene chloride) to provide the desired product. MS(ESI): 535.2 (M+H⁺)

Step 4: Preparation of[3-Hydroxycarbamoyl-4-(3-phenyl-pyrrolidine-1-carbonyl)-cyclohexyl]-methyl-carbamicacid tetrahydro-furan-3-yl ester

This compound was prepared using procedures analogous to those forExample 29 in step 5. MS (ESI): 460.2 (M+H⁺)

Example 35(3R)-tetrahydrofuran-3-yl((3S,4S)-3-[(hydroxyamino)carbonyl]-4-{[(3R)-3-phenylpyrrolidin-1-yl]carbonyl}cyclohexyl)methylcarbamate

This compound was prepared using procedures analogous to those forExample 34. MS (ESI): 460.2 (M+H⁺)

Example 36tetrahydro-2H-pyran-4-yl((3S,4S)-3-[(hydroxyamino)carbonyl]-4-{[(3R)-3-phenylpyrrolidin-1-yl]carbonyl}cyclohexyl)methylcarbamate

This compound was prepared using procedures analogous to those forExample 34. MS (ESI): 474.2 (M+H⁺)

Example 37(1S,3S,4S)-3-[(hydroxyamino)carbonyl]-4-{[(3R)-3-phenylpyrrolidin-1-yl]carbonyl}cyclohexylpyrrolidine-1-carboxylate Step 1: Preparation of5-(4-Nitro-phenoxycarbonyloxy)-2-(3-phenyl-pyrrolidine-1-carbonyl)-cyclohexa-2,3-dicarboxylicacid benzyl ester

To a solution of p-nitrophenyl chloroformate (181 mg) in methylenechloride was added5-hydroxy-2-(3-phenyl-pyrrolidine-1-carbonyl)-cyclohexanecarboxylic acidbenzyl ester (183 mg), followed by NMM (99 μL). After stirring thereaction condition for 60 h the volatiles were removed in-vacuo. Theresidue was purified by flash chromatography (eluting with 5% methanolin methylene chloride) to provide the carbamate compound. MS (ESI):573.2 (M+H⁺)

Step 2: preparation of Pyrrolidine-1-carboxylic acid3-benzyloxycarbonyl-4-(3-phenyl-pyrrolidine-1-carbonyl)-cyclohexyl ester

This compound was prepared using procedures analogous to Example 34,step 3. MS (ESI): 505.2 (M+H⁺).

Step 3: Preparation of Pyrrolidine-1-carboxylic acid3-hydroxycarbamoyl-4-(3-phenyl-pyrrolidine-1-carbonyl)-cyclohexyl ester

This compound was prepared using procedures analogous to those forExample 29 in step 5. MS (ESI): 430.3 (M+H⁺) 315.2 (M-114)⁺

Example 38(1S,3S,4S)-3-[(hydroxyamino)carbonyl]-4-{[(3R)-3-phenylpyrrolidin-1-yl]carbonyl}cyclohexylmethylcarbamate

This compound was prepared using procedures analogous to those forExample 37. MS (ESI): 390.2 (M+H⁺) 315.2 (M-114)⁺

Example 39(1S,3S,4S)-3-[(hydroxyamino)carbonyl]-4-{[(3R)-3-phenylpyrrolidin-1-yl]carbonyl}cyclohexyldimethylcarbamate

This compound was prepared using procedures analogous to those forExample 37. MS (ESI): 404.3 (M+H⁺) 315.2 (M-114)⁺

Example 40(1S,3S,4S)-3-[(hydroxyamino)carbonyl]-4-{[(3R)-3-phenylpyrrolidin-1-yl]carbonyl}cyclohexylmorpholine-4-carboxylate

This compound was prepared using procedures analogous to those forExample 37. MS (ESI): 446.2 (M+H⁺) 315.2 (M-114)⁺

Example 41(1S,3S,4S)-3-[(hydroxyamino)carbonyl]-4-{[(3R)-3-phenylpyrrolidin-1-yl]carbonyl}cyclohexyl(3R)-3-hydroxypyrrolidine-1-carboxylate

This compound was prepared using procedures analogous to those forExample 37. MS (ESI): 446.3 (M+H⁺) 315.2 (M-114)⁺

Example 42(3S)-tetrahydrofuran-3-yl(2S,3S)-3-[(hydroxyamino)carbonyl]-2-{[4-(3-isopropylphenyl)piperidin-1-yl]carbonyl}piperidine-1-carboxylateStep 1. tert-Butyl4-[(trifluoromethyl)sulfonyl]oxy-3,6-dihydropyridine-1(2H)-carboxylate

To a solution of tert-butyl 4-oxo-1-piperidinecarboxylate (10.50 g,0.05270 mol) in tetrahydrofuran (200.0 mL, 2.466 mol) at −78 Celsius,under nitrogen, was added 1.00 M of lithium hexamethyldisilazide intetrahydrofuran (55.96 mL). After stirred at −78 Celsius for 1 h, to theresultant mixture was added solidN-phenylbis(trifluoromethane-sulfonamide) (20.00 g, 0.05598 mol). Thereaction mixture was stirred at −78 Celsius for 2 h, then allowed towarm to rt gradually and stirred at rt overnight. After evaporation ofTHF under reduced pressure, the residue was diluted with ether. Themixture was washed with 1N HCl, 1N NaOH, and brine, successively. Theorganic layers were then dried and evaporated to dry. The residue wasapplied on silica gel column, eluting 0 to 20% ethyl acetate in hexane,to provide the enol triflate (17.46 g, 84%). MS (ESI): (-Boc) 232.0.

Step 2. tert-Butyl4-(3-isopropylphenyl)-3,6-dihydropyridine-1(2H)-carboxylate

A mixture of tert-butyl4-[(trifluoromethyl)sulfonyl]oxy-3,6-dihydropyridine-1(2H)-carboxylate(11.0 g, 0.0332 mol), (3-isopropylphenyl)boronic acid (5.44 g, 0.0332mol) and potassium phosphate (21.1 g, 0.0996 mol) in tetrahydrofuran(150.0 mL, 1.849 mol) was degassed for 15 min, thentetrakis(triphenylphosphine)palladium(0) (2 g, 0.002 mol) was added andthe resulting mixture was refluxed overnight. After evaporation of mostof THF, the residue was diluted with water, extracted with EtOAc. Thecombined organic layers were washed with brine, dried and evaporated todry. The residue was applied on silica gel column, eluting with 0 to 20%EtOAc in hexane (9.1 g, 91%). MS (ESI): (M-Bu) 246.1.

Step 3: De-Boc

tert-Butyl 4-(3-isopropylphenyl)-3,6-dihydropyridine-1(2H)-carboxylate(2.54 g, 0.00844 mol) was treated with 10 mL of TFA at rt for 30 min.After evaporation of TFA, the residue was exposed on high vacuum andthen used directly in next step.

Step 4: Preparation of2-[4-(3-Isopropyl-phenyl-3,6-dihydro-2H-pyridine-1-carbonyl]-piperidine-3-carboxylicacid tert-butyl ester

To a 0° C. solution of piperidine-2,3-dicarboxylic acid 3-tert-butylester (100 mg) in DMF (0.6 mL) was added sequentially,4-(3-isopropyl-phenyl)-1,2,3,6-tetrahydropyridine (97 mg). PyBOP (232mg), and diisopropylethylamine (0.152 mL). The resultant mixture wasstirred at rt overnight. The reaction solution was diluted with EtOAcand washed with saturated NaHCO₃ solution (×3), water, and brine. Theorganic layers were dried over MgSO₄, filtered, and concentrated to dryunder reduced pressure. The residue was used in next step withoutfurther purifications. MS (ESI): 413.2 (M+H⁺)

Step 5: Preparation of2-[4-(3-Isopropyl-phenyl)-3,6-dihydro-2H-pyridine-1-carbonyl]-piperidine-3-carboxylicacid benzyloxy-amide

To a solution of the crude product made above in methylene chloride (1.3mL) was added TFA (3.5 mL) followed by water (0.3 mL). The mixture wasstirred at rt overnight and then concentrated to dry under reducedpressure. The residue was co-evaporated several times with benzene toremove water. The residue was dissolved in DMF (1 mL) and cooled to 0°C., prior to the sequential addition of O-benzylhydroxyamine (83 mg),PyBOP (249 mg), and diisopropylethylamine (0.31 mL). The resultantmixture was stirred at rt overnight. The reaction solution was dilutedwith EtOAc and washed with saturated NaHCO₃ solution (×3), water, andbrine. The organic layers were dried over MgSO₄, filtered andconcentrated to dry under reduced pressure. The residue was purified byflash chromatography (eluting with 10% methanol in methylene chloride)to provide the desired product. MS (ESI): 462.2 (M+H⁺)

Step 6: Preparation of3-Benzyloxycarbamoyl-2-[4-(3-isopropyl-phenyl)-3,6-dihydro-2H-pyridine-1-carbonyl]-piperidine-1-carboxylicacid tetrahydro-furan-3-yl ester

To a solution of the compound made above (50 mg) in THF (0.5 mL) wasadded DIEA (40 μL) and carbonic acid 4-nitro-phenyl estertetrahydro-furan-3-yl ester (30 mg) in THF (0.5 mL). After stirring thereaction mixture at rt for 24 h, the volatiles were removed underreduced pressure. The residue was purified by flash chromatography(eluting with 7% methanol in methylene chloride) to provide the titledcompound. MS (ESI): 576.3 (M+H⁺)

Step 7: Preparation of3-Hydroxycarbamoyl-2-[4-(3-isopropyl-phenyl)-piperidine-1-carbonyl]-piperidine-1-carboxylicacid tetrahydro-furan-3-yl ester

To a solution of the compound made above in methanol (1 mL) was addedpalladium on carbon (20 mg). The suspension was stirred under hydrogenballoon for 3 h. The mixture was filtered and concentrated to dry underreduced pressure. The residue was purified by preparative HPLC to affordthe final product. MS (ESI): 488.2 (M+H⁺)

Example 43(3R)-tetrahydrofuran-3-yl(2S,3S)-3-[(hydroxyamino)carbonyl]-2-{[4-(3-isopropylphenyl)piperidin-1-yl]carbonyl}piperidine-1-carboxylate

This compound was prepared using procedures analogous to those forExample 42. MS (ESI): 488.2 (M+H⁺)

Example 44tetrahydro-2H-pyran-4-yl(2S,3S)-3-[(hydroxyamino)carbonyl]-2-{[4-(3-isopropylphenyl)piperidin-1-yl]carbonyl}piperidine-1-carboxylate

This compound was prepared using procedures analogous to those forExample 42. MS (ESI): 502.2 (M+H⁺)

Example 45(3R)-tetrahydrofuran-3-yl(2S,3S)-3-[(hydroxyamino)carbonyl]-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1-carboxylate

This compound was prepared using procedures analogous to those forExample 42. MS (ESI): 447.2 (M+H⁺)

Example 46(3S)-tetrahydrofuran-3-yl(2S,3S)-3-[(hydroxyamino)carbonyl]-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1-carboxylate

This compound was prepared using procedures analogous to those forExample 42. MS (ESI): 447.2 (M+H⁺)

Example 47tetrahydro-2H-pyran-4-yl(2S,3S)-3-[(hydroxyamino)carbonyl]-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1-carboxylate

This compound was prepared using procedures analogous to those forExample 42. MS (ESI): 461.2 (M+H⁺)

Example 48 Benzyl{5-[({(5S,6S)-5-[(hydroxyamino)carbonyl]-6-[(3-phenylpyrrolidin-1-yl)carbonyl]piperidin-3-yl}acetyl)amino]pentyl}carbamatePart 1: 1,2-dibenzyl3-tert-butyl(2S,3S)-5-oxopiperidine-1,2,3-tricarboxylate

To an oven-dried 5 mL conical vial equipped with a magnetic stir bar andunder a nitrogen gas atmosphere was placed oxalyl chloride (0.080 mL,0.92 mmol) and methylene chloride (0.7 mL). The solution was cooled to78° C. prior to the dropwise addition of dimethyl sulfoxide (0.080 mL,1.13 mmol) in methylene chloride (0.3 mL). After stirring the solutionfor 45 min, a solution of 1,2-dibenzyl3-tert-butyl(2S,3S)-5-hydroxypiperidine-1,2,3-tricarboxylate (266 mg,0.567 mmol) in methylene chloride (1 mL) was added dropwise and thesolution was allowed to gradually warm to ca. 0° C. over 1.5 h. Thereaction mixture was cooled to 78° C. prior to the dropwise addition oftriethylamine (0.240 mL, 1.72 mmol) and stirring was continued for 3 hwith gradual warming to ca. 0° C. The reaction was quenched by thedropwise addition of 5% citric acid (2 mL) and diluted with methylenechloride (15 mL). The organic layer was washed with brine (2×5 mL),dried (NaSO₄), and concentrated in-vacuo to afford 264 mg (100%) of thedesired ketone as a sticky yellow oil. LCMS (ESI): 490 (M+Na⁺)

Part 2: 1,2-dibenzyl3-tert-butyl(2S,3S)-5-(2-methoxy-2-oxoethylidene)piperidine-1,2,3-tricarboxylate

To an oven-dried 25 mL round-bottomed flask equipped with a magneticstir bar and under a nitrogen gas atmosphere was placedmethyl(triphenylphosphoranylidene)acetate (199 mg, 0.597 mmol) andtoluene (5 mL). To this heterogeneous solution was added a solution of1,2-dibenzyl 3-tert-butyl(2S,3S)-5-oxopiperidine-1,2,3-tricarboxylate(93 mg, 0.199 mmol) in toluene (3 mL). The reaction mixture was heatedto reflux and stirred overnight. The volatiles were then removedin-vacuo and the yellow oil was purified by Combiflash (10 to 30% ethylacetate in hexanes) to afford 83 mg (80%) of 1,2-dibenzyl3-tert-butyl(2S,3S)-5-(2-methoxy-2-oxoethylidene)piperidine-1,2,3-tricarboxylate.LCMS (ESI): 424 (M-CO₂t-Bu+2H⁺), 468 (M-t-Bu+2H⁺), 524 (M+H⁺).

Part 3:(2S,3S)-3-(tert-butoxycarbonyl)-5-(2-methoxy-2-oxoethyl)piperidine-2-carboxylicacid

A solution of 1,2-dibenzyl3-tert-butyl(2S,3S)-5-(2-methoxy-2-oxoethylidene)piperidine-1,2,3-tricarboxylate(98 mg, 0.188) in methanol (5 mL) was hydrogenated in the presence of10% palladium on carbon (100 mg, 0.094), under balloon pressure ofhydrogen, overnight. The resulting reaction mixture was filtered througha pad of celite and the precipitate was washed with methanol (2×5 mL).The volatiles were removed in-vacuo to afford 50 mg (88%) of(2S,3S)-3-(tert-butoxycarbonyl)-5-(2-methoxy-2-oxoethyl)piperidine-2-carboxylicacid as a sticky amorphous solid, which was used directly in thefollowing coupling without further purification. LCMS (ESI): 246(M-t-Bu+H⁺), 302 (M+H⁺).

Part 4:tert-butyl(2S,3S)-5-(2-methoxy-2-oxoethyl)-2-[(3-phenylpyrrolidin-1-yl)carbonyl]piperidine-3-carboxylate

To an oven-dried 5 mL conical vial equipped with a magnetic stir bar andunder a nitrogen gas atmosphere was placed sequentially:(2S,3S)-3-(tert-butoxycarbonyl)-5-(2-methoxy-2-oxoethyl)piperidine-2-carboxylicacid (50 mg, 0.166 mmol), anhydrous DMF (2 mL), BOP reagent (100 mg,0.226 mmol), 3-phenyl-pyrrolidine (25 mg, 0.17 mmol), andN,N-diisopropyl ethylamine (0.086 mL, 0.49 mmol). After stirring thereaction mixture overnight, the reaction was quenched with 5% citricacid (1 mL) and the reaction mixture was diluted with ethyl acetate (15mL) and water (4 mL). The aqueous layer was extracted with ethyl acetate(3×3 mL) and the combined organic phases were washed with saturatedsodium bicarbonate (3×5 mL), brine (5 mL), dried (NaSO₄), andconcentrated in-vacuo to afford 75 mg of crude product that was useddirectly in the following hydrolysis. LCMS (ESI): 431 (M+H), 375(M-t-Bu+2H⁺).

Part 5:{(5S,6S)-5-(tert-butoxycarbonyl)-6-[(3-phenylpyrrolidin-1-yl)carbonyl]piperidin-3-yl}aceticacid

A solution oftert-butyl(2S,3S)-5-(2-methoxy-2-oxoethyl)-2-[(3-phenylpyrrolidin-1-yl)carbonyl]piperidine-3-carboxylatein THF (3 mL) was cooled to 0° C. prior to the addition of lithiumhydroxide (7 mg, 0.16 mmol). After warming to ambient temperature, thereaction mixture was stirred overnight. The volatiles were removedin-vacuo to afford 60 mg (87%) of{(5S,6S)-5-(tert-butoxycarbonyl)-6-[(3-phenylpyrrolidin-1-yl)carbonyl]piperidin-3-yl}aceticacid as an off-white solid that was used without neutralization andpurification in the following coupling reaction. MS (ESI): 417 (M+H⁺).

Part 6:tert-Butyl(2S,3S)-5-{2-[(5-{[(benzyloxy)carbonyl]amino}pentyl)amino]-2-oxoethyl}-2-[(3-phenylpyrrolidin-1-yl)carbonyl]piperidine-3-carboxylate

To an oven-dried 5 mL conical vial equipped with a magnetic stir bar andunder a nitrogen gas atmosphere was placed sequentially:{(5S,6S)-5-(tert-butoxycarbonyl)-6-[(3-phenylpyrrolidin-1-yl)carbonyl]piperidin-3-yl}aceticacid (60 mg, 0.144 mmol), anhydrous DMF (2 mL), BOP reagent (100 mg,0.226 mmol), N,N-Cbz-1,5-diaminopentane hydrochloride (45 mg, 0.17mmol), and N,N-diisopropyl ethylamine (0.086 mL, 0.49 mmol). Afterstirring the reaction mixture overnight, the reaction was quenched with5% citric acid (1 mL) and the reaction mixture was diluted with ethylacetate (15 mL) and water (4 mL). The aqueous layer was extracted withethyl acetate (3×3 mL) and the combined organic phases were washed withsaturated sodium bicarbonate (3×5 mL), brine (5 mL), dried (NaSO₄), andconcentrated in-vacuo. Purification by Combiflash (0 to 10% methanol inmethylene chloride over 25 min) to afford 56 mg (62%) oftert-butyl(2S,3S)-5-{2-[(5-{[(benzyloxy)carbonyl]amino}pentyl)amino]-2-oxoethyl}-2-[(3-phenylpyrrolidin-1-yl)carbonyl]piperidine-3-carboxylate.LCMS (ESI): 635 (M+H⁺), 636 (M+2H⁺).

Part 7:(2S,3S)-5-{2-[(5-{[(benzyloxy)carbonyl]amino}pentyl)amino]-2-oxoethyl}-2-[(3-phenylpyrrolidin-1-yl)carbonyl]piperidine-3-carboxylicacid

A solution oftert-butyl(2S,3S)-5-{2-[(5-{[(benzyloxy)carbonyl]amino}pentyl)amino]-2-oxoethyl}-2[(3-phenylpyrrolidin-1-yl)carbonyl]piperidine-3-carboxylate(40 mg, 0.063 mmol) in methylene chloride (2 mL) was added a drop ofwater and trifluoroacetic acid (4 mL). After stirring the reactionmixture overnight, the volatiles were removed in-vacuo and the residuewas azeotropically washed with benzene (2×3 mL) and heptane (2×3 mL).The crude product was dried under high vacuum and used directly in thefollowing coupling reaction without purification. MS (ESI): 579 (M+H).

Part 8: Benzyl{5-[({(5S,6S)-5-[(hydroxyamino)carbonyl]-6-[(3-phenylpyrrolidin-1-yl)carbonyl]piperidin-3-yl}acetyl)amino]pentyl}carbamate

To an oven-dried 5 mL conical vial equipped with a magnetic stir bar andunder a nitrogen gas atmosphere was placed sequentially:(2S,3S)-5-{2-[(5-{[(benzyloxy)carbonyl]amino}pentyl)amino]-2-oxoethyl}-2-[(3-phenylpyrrolidin-1-yl)carbonyl]piperidine-3-carboxylicacid (0.063 mmol), anhydrous DMF (1.5 mL), PyBOP reagent (40 mg, 0.076mmol), hydroxylamine hydrochloride (20 mg, 0.289 mmol), and 4-methylmorpholine (0.046 mL, 0.42 mmol). After stirring overnight, the crudereaction mixture was directly applied to preparative HPLC purificationto afford 14 mg (38% for 2 steps) of pure{7-[5-(S)-hydroxycarbomyl-6-(R)-(3-phenyl-pyrrolidine-1-carbonyl)-piperidine-3-yl]-6-oxo-heptyl}-carbamicacid benzyl ester. LCMS (ESI): 594 (M+H⁺), 595 (M+2⁺).

Example 49(2S,3S)-5-{2-[(5-aminopentyl)amino]-2-oxoethyl}-N-hydroxy-2-[(3-phenylpyrrolidin-1-yl)carbonyl]piperidine-3-carboxamide

A solution of{7-[5-(S)-hydroxycarbomyl-6-(R)-(3-phenyl-pyrrolidine-1-carbonyl)-piperidine-3-yl]-6-oxo-heptyl}-carbamicacid benzyl ester (10 mg, 0.0169 mmol) in methanol (2 mL) washydrogenated using palladium on barium sulfate (5%) (10 mg, 0.0047 mmol)and under balloon pressure of hydrogen. After stirring for 4 h, thereaction mixture was filtered through a pad of celite and theprecipitate was washed with methanol (2×5 mL). The volatiles wereremoved in-vacuo to afford 6.5 mg (84%) of5-(7-amino-2-oxo-heptyl)-2-(R)-(3-phenyl-pyrrolidine-1-carbonyl)-piperidine-3-(S)-carboxylicacid hydroxyamide. LCMS (ESI): 460 (M+Fr).

Example 50(1S,2S)—N-Hydroxy-5-(2-oxo-2-piperidin-1-ylethyl)-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxamidePart 1:4-Methoxycarbonylmethylidene-cyclohexane-1-(S)-2-(S)-dicarboxylic acid2-(S)-benzyl ester 1-(S)-tert-butyl ester

To an oven-dried 50 mL round-bottomed flask equipped with a magneticstir bar and under a nitrogen gas atmosphere was placed4-oxo-cyclohexane-1-(S)-2-(S)-dicarboxylic acid 2-(S)-benzyl ester1-(S)-tert-butyl ester (470 mg, 1.42 mmol), toluene (35 mL), andmethyl(triphenylphosphoranylidene)acetate (2.4 g, 7.2 mmol). Theheterogeneous mixture was heated to reflux and stirred overnight. Thevolatiles were then removed in-vacuo and the yellow oil was purified byCombiflash (10 to 30% ethyl acetate in hexanes) to afford 496 mg (85%)of 4 methoxycarbonyl-methylidene-cyclohexane-1-(S)-2-(S)-dicarboxylicacid 2-(S)-benzyl ester 1-(S)-tert-butyl ester. LCMS (ESI): 301(M−CO₂(t-Bu)−Me+3H⁺), 411 (M+Na⁺).

Part 2:4-Methoxvcarbonylmethylidene-cyclohexane-1-(S)-2-(S)-dicarboxylic acid2-(S)-benzyl ester

A solution of4-methoxycarbonyl-methylidene-cyclohexane-1-(S)-2-(S)-dicarboxylic acid2-benzyl ester 1-tert-butyl ester (496 mg, 1.21 mmol) in methylenechloride (8 mL) was added a couple of drops of water and trifluoroaceticacid (16 mL). After stirring the reaction mixture for 3 h, the volatileswere removed in-vacuo and the residue was azeotropically washed withbenzene (2×5 mL), heptane (2×5 mL), and toluene (2×5 mL). The crudeproduct was dried under high vacuum and used directly in the followingcoupling reaction without further purification. MS (ESI): 355 (M+Na⁺).

Part 3:5-Methoxycarbonylmethylidene-2-(S)-(4-phenyl-piperazine-1-carbonyl)-cyclohexane-(S)-carboxylicacid benzyl ester

To an oven-dried 10 mL conical vial equipped with a magnetic stir barand under a nitrogen gas atmosphere was placed sequentially:4-methoxycarbonylmethylidene-cyclohexane-1-(S)-2-(S)-dicarboxylic acid2-(S)-benzyl ester (172 mg, 0.52 mmol), anhydrous DMF (4 mL), PyBOPreagent (324 mg, 0.62 mmol), N-phenyl piperazine (0.10 mL, 0.655 mmol),and 4-methyl morpholine (0.220 mL, 2.02 mmol). After stirring thereaction mixture overnight, the reaction was quenched with 5% citricacid (1 mL) and the reaction mixture was diluted with ethyl acetate (15mL) and water (4 mL). The aqueous layer was extracted with ethyl acetate(3×3 mL) and the combined organic phases were washed with saturatedsodium bicarbonate (3×5 mL), brine (5 mL), dried (Na₂SO₄), andconcentrated in-vacuo. Purification by Combiflash (0 to 10% methanol inmethylene chloride over 30 min) to afford 233 mg (94%) of pure 5methoxycarbonylmethylidene-2-(S)-(4-phenyl-piperazine-1-carbonyl)-cyclohexane-(S)-carboxylicacid benzyl ester. LCMS (ESI): 477 (M+H⁺).

Part 4:5-Methoxycarbonylmethylidene-2-(S)-(4-phenyl-piperazine-1-carbonyl)-cyclohexane-(S)-carboxylicacid

A solution of 5methoxycarbonylmethylidene-2-(S)-(4-phenyl-piperazine-1-carbonyl)-cyclohexane-(S)-carboxylicacid benzyl ester (233 mg, 0.49) in methanol (5 mL) was hydrogenated inthe presence of 10% palladium on carbon (150 mg, 0.14), under balloonpressure of hydrogen, for 2 h. The resulting reaction mixture wasfiltered through a pad of celite and the precipitate was washed withmethanol (2×5 mL). The volatiles were removed in-vacuo to afford 172 mg(90%) of 5methoxy-carbonylmethylidene-2-(S)-(4-phenyl-piperazine-1-carbonyl)-cyclohexane-(S)-carboxylicacid as a sticky oil, which was used directly in the following couplingwithout further purification. LCMS (ESI): 389 (M+H⁺).

Part 5:[3-(S)-Benyloxycarbamoyl-4-(S)-(4-phenyl-piperazine-1-carbonyl)-cyclohexyl]-aceticacid methyl ester

To an oven-dried 5 mL conical vial equipped with a magnetic stir bar andunder a nitrogen gas atmosphere was placed sequentially: 5-methoxycarbonyl-methylene-2-(S)-(4-phenyl-piperazine-1-carbonyl)-cyclohexane-(S)-carboxylicacid (172 mg, 0.44 mmol), anhydrous DMF (3 mL), PyBOP reagent (320 mg,0.61 mmol), O-benzyl-hydroxylamine hydrochloride (100 mg, 0.627 mmol),and 4-methyl morpholine (0.160 mL, 1.47 mmol). After stirring thereaction mixture overnight, the reaction was quenched with 5% citricacid (1 mL) and the reaction mixture was diluted with ethyl acetate (15mL) and water (4 mL). The aqueous layer was extracted with ethyl acetate(3×3 mL) and the combined organic phases were washed with saturatedsodium bicarbonate (3×5 mL), brine (5 mL), dried (NaSO4), andconcentrated in-vacuo. Purification by Combiflash (0 to 15% methanol inmethylene chloride over 30 min) to afford 213 mg (98%) of pure[3-(S)-benyloxycarbamoyl-4-(S)-(4-phenyl-piperazine-1-carbonyl)-cyclohexyl]-aceticacid methyl ester. LCMS (ESI): 494 (M+H⁺).

Part 6:[3-(S)-Benyloxycarbamoyl-4-(S)-(4-phenyl-piperazine-1-carbonyl)-cyclohexyl]-aceticacid

To a solution of[3-(S)-benyloxycarbamoyl-4-(S)-(4-phenyl-piperazine-1-carbonyl)-cyclohexyl]-aceticacid methyl ester (213 mg, 0.432 mmol) in THF (5 mL) was added water (3mL) and lithium hydroxide (40 mg, 0.95 mmol). After stirring at ambienttemperature for 4 h, the reaction mixture was acidified with 1 N HCl toa pH of ca. 5. The product was extracted with ethyl acetate (4×5 mL) andthe combined organic layers were washed with brine (5 mL), dried(NaSO₄), and the volatiles were removed in-vacuo to afford 154 mg (87%)of[3-(S)-benyloxycarbamoyl-4-(S)-(4-phenyl-piperazine-1-carbonyl)-cyclohexyl]-aceticacid as a sticky oil that was used without further purification in thefollowing coupling reaction. MS (ESI): 480 (M+H⁺).

Part 7:5-(2-Oxo-2-piperidin-1-yl-ethyl)-2-(S)-(4-phenyl-piperazine-1-carbonyl)-cyclohexan-(S)-carboxylicacid benzyloxy-amide

To an oven-dried 5 mL conical vial equipped with a magnetic stir bar andunder a nitrogen gas atmosphere was placed sequentially:[3-(S)-benyloxycarbamoyl-4-(S)-(4-phenyl-piperazine-1-carbonyl)-cyclohexyl]-aceticacid (16 mg, 0.033 mmol), anhydrous DMF (1 mL), PyBOP reagent (20 mg,0.038 mmol), piperidine (0.010 mL, 0.101 mmol), and 4-methyl morpholine(0.01 mL, 0.092 mmol). After stirring the reaction mixture overnight,the reaction was quenched with 5% citric acid (1 mL) and the reactionmixture was diluted with ethyl acetate (15 mL) and water (4 mL). Theaqueous layer was extracted with ethyl acetate (3×3 mL) and the combinedorganic phases were washed with saturated sodium bicarbonate (3×5 mL),brine (5 mL), dried (NaSO₄), and concentrated in-vacuo. Purification byCombiflash (0 to 10% methanol in methylene chloride over 30 min) toafford 17 mg (94%) of pure5-(2-oxo-2-piperidin-1-yl-ethyl)-2-(S)-(4-phenyl-piperazine-1-carbonyl)-cyclohexan-(S)-carboxylicacid benzyloxy-amide. LCMS (ESI): 547 (M+H⁺).

Part 8:5-(2-Oxo-2-piperidin-1-yl-ethyl)-2-(S)-(4-phenyl-piperazine-1-carbonyl-cyclohexan-(S)-carboxylicacid hydroxyamide

A solution of5-(2-oxo-2-piperidin-1-yl-ethyl)-2(S)-(4-phenyl-piperazine-1-carbonyl-cyclohexan-(S)-carboxylicacid benzyloxy-amide (16 mg, 0.029 mmol) in methanol (2 mL) washydrogenated using palladium on barium sulfate (5%) (40 mg, 0.018 mmol)and under balloon pressure of hydrogen. After stirring for 6 h, thereaction mixture was filtered through a pad of celite and theprecipitate was washed with methanol (2×5 mL). The volatiles wereremoved in-vacuo and the residue was purified by preparative HPLC(gradient of 0 to 40% of 0.1% TFA in acetonitrile to 0.1% TFA in waterover 30 min) to afford 6 mg (46%) of5-(2-oxo-2-piperidin-1-yl-ethyl)-2-(S)-(4-phenyl-piperazine-1-carbonyl-cyclohexan-(S)-carboxylicacid hydroxyamide as a white solid. LCMS (ESI): 457 (M+H⁺).

Example 51(1S,2S)—N-Hydroxy-5-(2-oxo-2-pyrrolidin-1-ylethyl)-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxamide

The title compound was prepared using the general procedure that wasoutlined above. The amide coupling, described above in part 7 for theanalogous compound, afforded 18 mg (100%) of5-(2-oxo-2-pyrrolidin-1-yl-ethyl)-2-(S)-(4-phenyl-piperazine-1-carbonyl-cyclohexancarboxylicacid benzyloxy-amide LCMS (ESI): 533 (M+H⁺). Subsequent hydrogenation toremove the benzyl group, described above in part 8 for the analogouscompound, afforded 7 mg (46%) of5-(2-oxo-2-pyrrolidin-1-yl-ethyl)-2-(S)-(4-phenyl-piperazine-1-carbonyl-cyclohexan-(S)-carboxylicacid hydroxyamide as a white solid. LCMS (ESI): 443 (M+H⁺).

Example 52(1S,2S)—N-hydroxy-5-{2-[(3R)-3-hydroxypyrrolidin-1-yl]-2-oxoethyl}-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxamide

The title compound was prepared using the general procedure that wasoutlined above. The amide coupling, described above in part 7 for theanalogous compound, afforded 13 mg (72%) of5-[2-oxo-2-(3-R-hydroxypyrrolidin-1-yl-ethyl]-2-(S)-(4-phenyl-piperazine-1-carbonyl-cyclohexan-(S)-carboxylicacid benzyloxy-amide LCMS (ESI): 549 (M+H⁺). Subsequent hydrogenation toremove the benzyl group, described above in part 8 for the analogouscompound, afforded 5 mg (45%) of5-[2-oxo-2-(3-(R)-hydroxypyrrolidin-1-yl-ethyl)-2-(S)-(4-phenyl-piperazine-1-carbonyl-cyclohexan-(S)-carboxylicacid hydroxyamide as a white solid. LCMS (ESI): 459 (M+H⁺).

Example 53(1S,2S)—N(2)-hydroxy-N(1)-{4-[(2-methylquinolin-4-yl)methoxy]phenyl}-4-(2-oxo-2-piperidin-1-ylethyl)cyclohexane-1,2-dicarboxamidePart 1: 4-Hydroxymethyl-2-methyl quinoline

To a 25 mL round-bottomed flask equipped with a magnetic stirrer andunder a N2 (g) purge was placed sequentially: quinaldine (0.57 g, 4.0mmol), methanol (8 mL), and water (4 mL). The solution was cooled to 0°C. prior to the sequential addition of: concentrated sulfuric acid (0.2mL, 4 mmol), iron (II) sulfate heptahydrate (0.33 g, 1.2 mmol), and ironpowder (0.067 g, 1.2 mmol). After stirring the heterogeneous mixture for10 min, hydroxylamine-O-sulfonic acid (HOSA) (1.36 g, 12 mmol) was addedand the resulting mixture was stirred for 6 h prior to quenching thereaction with 50% NaOH until the pH was ca. 10. The brown solution wasfiltered through a pad of celite and then extracted with methylenechloride (4×15 mL). The combined organic phases were washed with water(20 mL), brine (15 mL), dried (NaSO₄), and concentrated in-vacuo toafford a brown solid that was purified by Combiflash (0 to 60% ethylacetate in hexanes over 30 min) to afford 360 mg (52%) of pure4-hydroxymethyl-2-methyl quinoline. LCMS (ESI): 174 (M+H′).

Part 2: 4-Chloromethyl-2-methyl quinoline

4-hydroxymethyl-2-methyl quinoline (7.0 g, 40 mmol) was dissolved inchloroform (150 mL) and cooled to 0° C., thionyl chloride (15.0 mL) wasadded slowly at this temperature and then the reaction mixture wasallowed to warm up to room temperature and stirred overnight. Thesolvent was removed in-vacuo and the residue was titureted with ethylacetate/ethyl ether to provide 9.0 g (100%) of 4-chloromethyl-2-methylquinoline as an HCl salt. MS (ESI): 191.9 (M+H⁺).

Part 3: tert-Butyl N-(4-hydroxyphenyl) carbamate

To a dry 250 mL round-bottomed flask equipped with a magnetic stir barand rubber septa with N2 (g) inlet was placed 4-amino phenol (5.0 g,45.8 mmol) and THF (50 mL). The heterogeneous solution was cooled to 0°C. prior to the addition of di-tert-butyl dicarbonate (12 g, 55 mmol).Upon addition heat was observed and the cloudy solution becametranslucent. The solution was allowed to gradually warm to ambienttemperature and stirred overnight. The volatiles were removed in-vacuoto afford tert-butyl N-(4-hydroxyphenyl) carbamate (11.3 g). LCMS (ESI):154 (M-t-Bu+2H⁺), 232 (M+Na⁺).

Part 4: [4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-carbamic acidtert-butyl ester

To a 500 mL round-bottomed flask equipped with magnetic stir bar wasplaced 4-chloromethyl-2-methyl quinoline (6.84 g, 30.0 mmol), tert-butylN-(4-hydroxyphenyl) carbamate (6.24 g, 30.0 mmol), Cs₂CO₃ (20.0 g, 60.0mmol), and n-Bu₄NI (11.1 g, 30.0 mmol) in DMSO (150 mL). The solutionwas stirred at 80° C. for 3 h. After cooling to ambient temperature,cold water was added and the product was extracted with ethyl acetate.The combined extract was washed with water, brine, dried andconcentrated. Combiflash chromatography with CH₂Cl₂/EtOAc afforded 8.0 g(73%) of the desired product. MS (ESI): 365.3 (M+Hp.

Part 5: 4-(2-methyl-quinolin-4-ylmethoxy)-phenylamine hydrochloride

To a solution of [4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-carbamicacid tert-butyl ester (1.5 g, 4.1 mmol) in ethyl acetate (5 mL) wasadded 4 N HCl in dioxane (20 mL) and the mixture was stirred at roomtemperature for 3 h. Ethyl ether was then added and the precipitate wasfiltered and washed with ethyl ether to provide 1.3 g of the desiredfree amine as an HCl salt, which was used in the following reactionwithout further purification. MS (ESI): 265.0 (M+H⁺).

Part 6:5-Methoxycarbonylmethylene-2-(S)-[4-(2-methyl-quinolin-4-ylmethoxy)-phenylcarbamoyl]-cyclohexanecarboxylicacid 1-(S)-benzyl ester

To an oven-dried 10 mL conical vial equipped with a magnetic stir barand under a nitrogen gas atmosphere was placed sequentially:4-methoxycarbonylmethylene-cyclohexane-1-(S), 2-(S)-dicarboxylic acid2-(S)-benzyl ester (172 mg, 0.52 mmol), anhydrous DMF (4 mL), PyBOPreagent (324 mg, 0.62 mmol),4-(2-methyl-quinolin-4-ylmethoxy)-phenylamine hydrochloride (172 mg,0.655 mmol), and 4-methyl morpholine (0.30 mL, 2.76 mmol). Afterstirring the reaction mixture overnight, the reaction was quenched with5% citric acid (1 mL) and the reaction mixture was diluted with ethylacetate (15 mL) and water (4 mL). The aqueous layer was extracted withethyl acetate (3×3 mL) and the combined organic phases were washed withsaturated sodium bicarbonate (3×5 mL), brine (5 mL), dried (NaSO₄), andconcentrated in-vacuo. Purification by Combiflash (0 to 10% methanol inmethylene chloride over 30 min) to afford 267 mg (89%) of pure product.LCMS (ESI): 579 (M+H⁺).

Part 7:5-Methoxycarbonylmethyl-2-(S)-[4-(2-methylquinolin-4-ylmethoxy)-phenylcarbamoyl]-cyclohexane-(S)-carboxylicacid

A solution of benzyl methyl ester (267 mg, 0.46) in methanol (5 mL) washydrogenated in the presence of 10% palladium on carbon (150 mg, 0.14),under balloon pressure of hydrogen, for 2 h. The resulting reactionmixture was filtered through a pad of celite and the precipitate waswashed with methanol (2×5 mL). The volatiles were removed in-vacuo toafford 212 mg (94%) of the desired carboxylic acid as a sticky oil,which was used directly in the following coupling without furtherpurification. LCMS (ESI): 491 (M+H⁺).

Part 8:{3-(S)-Benzyloxycarbamoyl-4-(S)-[4-(2-methyl-quinolin-4-ylmethoxy)-phenylcarbamoyl]-cyclohexyl}-aceticacid methyl ester

To an oven-dried 5 mL conical vial equipped with a magnetic stir bar andunder a nitrogen gas atmosphere was placed sequentially:5-methoxycarbonylmethyl-2-(S)-[4-(2-methylquinolin-4-ylmethoxy)-phenylcarbamoyl]-cyclohexane-(S)-carboxylicacid (212 mg, 0.43 mmol), anhydrous DMF (3 mL), PyBOP reagent (320 mg,0.61 mmol), O-benzylhydroxylamine hydrochloride (100 mg, 0.627 mmol),and 4-methyl morpholine (0.160 mL, 1.47 mmol). After stirring thereaction mixture overnight, the reaction was quenched with 5% citricacid (1 mL) and the reaction mixture was diluted with ethyl acetate (15mL) and water (4 mL). The aqueous layer was extracted with ethyl acetate(3×3 mL) and the combined organic phases were washed with saturatedsodium bicarbonate (3×5 mL), brine (5 mL), dried (NaSO4), andconcentrated in-vacuo. Purification by Combiflash (0 to 15% methanol inmethylene chloride over 30 min) to afford 238 mg (93%) of the pureamide. LCMS (ESI): 596 (M+H⁺).

Part 9:{3-(S)-Benzyloxycarbamoyl-4-(S)-[4-(2-methyl-quinolin-4-ylmethoxy)-phenylcarbamoyl]-cyclohexyl}-aceticacid

To a solution of {3-(S)-benzyloxycarbamoyl-4-(S)-[4-(2-methyl-quinolin-4-ylmethoxy)-phenylcarbamoyl]-cyclohexyl}-aceticacid methyl ester (238 mg, 0.40 mmol) in THF (5 mL) was added water (3mL) and lithium hydroxide (40 mg, 0.95 mmol). After stirring at ambienttemperature for 4 h, the reaction mixture was acidified with 1 N HCl toa pH of ca. 5. The product was extracted with ethyl acetate (4×5 mL) andthe combined organic layers were washed with brine (5 mL), dried(NaSO₄), and the volatiles were removed in-vacuo to afford 210 mg (90%)of the desired carboxylic acid as a sticky oil that was used withoutfurther purification in the following coupling reaction. MS (ESI): 582(M+H⁺).

Part 10:4-(2-Oxo-2-piperidin-1-yl-ethyl)-cyclohexan-1-(S)-,2-(S)-dicarboxylicacid 2-(S)-(benzyloxy-amide)1-(S)-{[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-amide

To an oven-dried 5 mL conical vial equipped with a magnetic stir bar andunder a nitrogen gas atmosphere was placed sequentially:{3-(S)-benzyloxycarbamoyl-4-(S)-[4-(2-methyl-quinolin-4-ylmethoxy)-phenylcarbamoyl]-cyclohexyl}-aceticacid (20 mg, 0.034 mmol), anhydrous DMF (1 mL), PyBOP reagent (20 mg,0.038 mmol), piperidine (0.010 mL, 0.101 mmol), and 4-methyl morpholine(0.01 mL, 0.092 mmol). After stirring the reaction mixture overnight,the reaction was quenched with 5% citric acid (1 mL) and the reactionmixture was diluted with ethyl acetate (15 mL) and water (4 mL). Theaqueous layer was extracted with ethyl acetate (3×3 mL) and the combinedorganic phases were washed with saturated sodium bicarbonate (3×5 mL),brine (5 mL), dried (NaSO₄), and concentrated in-vacuo. Purification byCombiflash (0 to 10% methanol in methylene chloride over 30 min) toafford 21 mg (95%) of the desired amide. LCMS (ESI): 649 (M+1H).

Part 11:4-(2-Oxo-2-piperidin-1-yl-ethyl)-cyclohexane-1-(S)-,2-(S)-dicarboxylicacid 2-(S)-hydroxyamide1-{[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-amide}

A solution of 4-(2-oxo-2-piperidin-1-yl-ethyl)-cyclohexan-1-(5),2-(S)-dicarboxylic acid 2-(S)-(benzyloxy-amide)1-(S)-{[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-amide (18 mg, 0.028mmol) in methanol (2 mL) was hydrogenated using palladium on bariumsulfate (5%) (40 mg, 0.018 mmol) and under balloon pressure of hydrogen.After stirring for 6 h, the reaction mixture was filtered through a padof celite and the precipitate was washed with methanol (2×5 mL). Thevolatiles were removed in-vacuo and the residue was purified bypreparative HPLC (gradient of 0 to 40% of 0.1% TFA in acetonitrile to0.1% TFA in water over 30 min) to afford 10 mg (64%) of the desiredhydroxomic acid as a white solid. LCMS (ESI): 559 (M+H⁺).

The following compounds were made using the methods described andexemplified above.

Example 54(2S,3S,5R)-2-{[4-(3-isopropylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-N,5-dihydroxypiperidine-3-carboxamideand(2S,3S,5S)-2-{[4-(3-isopropylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-N,5-dihydroxypiperidine-3-carboxamide

These compounds were prepared using procedures analogous to those forexample 10. Ms (ESI): (M+H)⁺=388.3.

Example 55(2S,3S,5R)—N,5-dihydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-3-carboxamideand(2S,3S,5S)—N,5-dihydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-3-carboxamide

These compounds were prepared using procedures analogous to those forexample 10. Ms (ESI): (M+H)⁺=349.3.

Example 56(2S,3S,5R)—N-Hydroxy-5-(2-morpholin-4-yl-2-oxoethyl)-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-3-carboxamideand(2S,3S,5S)—N-Hydroxy-5-(2-morpholin-4-yl-2-oxoethyl)-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-3-carboxamide

These compounds were prepared using procedures analogous to those forexample 2. Ms (ESI): (M+H)⁺=460.3.

Example 57(2S,3S,5S)—N-5-dihydroxy-2-{[4-(3-isopropylphenyl)piperidin-1-yl]carbonyl}piperidine-3-carboxamideand(2S,3S,5R)—N,5-dihydroxy-2-{[4-(3-isopropylphenyl)piperidin-1-yl]carbonyl}piperidine-3-carboxamide

These compounds were prepared using procedures analogous to those forexample 10. Ms (ESI): (M+H)⁺=390.2.

Example 58(2S,3S,5R)—N-hydroxy-2-{[4-(3-isopropylphenyl)piperidin-1-yl]carbonyl}-5-(2-morpholin-4-yl-2-oxoethyl)piperidine-3-carboxamideand(2S,3S,5S)—N-hydroxy-2-{[4-(3-isopropylphenyl)piperidin-1-yl]carbonyl}-5-(2-morpholin-4-yl-2-oxoethyl)piperidine-3-carboxamide

These compounds were prepared using procedures analogous to those forexample 2. Ms (ESI): (M+H)⁺=501.3.

Example 59(1S,2S)—N-Hydroxy-5-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 50. Ms (ESI): (M+H)⁺=472.2.

Example 60(1S,2S)—N-Hydroxy-5-(2-morpholin-4-yl-2-oxoethyl)-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 50. Ms (ESI): (M+H)⁺=459.2.

Example 61(1S,2S)—N-Hydroxy-5-{2-[(2-methoxyethyl)amino]-2-oxoethyl}-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 50. Ms (ESI): (M+H)⁺=447.2.

Example 62(1S,3S,4S)-3-[(Hydroxyamino)carbonyl]-4-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexylmethylcarbamate

This compound was prepared using procedures analogous to those forexample 37. Ms (ESI): (M+H)⁺=405.1.

Example 63(1S,3S,4S)-3-[(Hydroxyamino)carbonyl]-4-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexyldimethylcarbamate

This compound was prepared using procedures analogous to those forexample 37. Ms (ESI): (M+H)⁺=419.1.

Example 64(1S,3S,4S)-3-[(Hydroxyamino)carbonyl]-4-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexylpyrrolidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 37. Ms (ESI): (M+H)⁺=445.1.

Example 65(1S,3S,4S)-3-[(Hydroxyamino)carbonyl]-4-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexylpiperidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 37. Ms (ESI): (M+H)⁺=459.2.

Example 66(1S,3S,4S)-3-[(Hydroxyamino)carbonyl]-4-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexylmorpholine-4-carboxylate

This compound was prepared using procedures analogous to those forexample 37. Ms (ESI): (M+H)⁺=461.1.

Example 67(1S,3S,4S)-3-[(Hydroxyamino)carbonyl]-4-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexyl(3R)-3-hydroxypyrrolidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 37. Ms (ESI): (M+H)⁺=461.1.

Example 68(1S,3S,4S)-3-[(Hydroxyamino)carbonyl]-4-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexylcyclopropylcarbamate

This compound was prepared using procedures analogous to those forexample 37. Ms (ESI): (M+H)⁺=431.1.

Example 69(3R,4S)—N-Hydroxy-1-(morpholin-4-ylcarbonyl)-4-[(4-phenylpiperidin-1-yl)carbonyl]piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 12. Ms (ESI): (M+H)⁺=445.2.

Example 70(3S,5S,6S)-5-[(Hydroxyamino)carbonyl]-1-methyl-6-{[(3R)-3-phenylpyrrolidin-1-yl]carbonyl}piperidin-3-ylpyrrolidine-1-carboxylate and(3R,5S,6S)-5-[(Hydroxyamino)carbonyl]-1-methyl-6-{[(3R)-3-phenylpyrrolidin-1-yl]carbonyl}piperidin-3-ylpyrrolidine-1-carboxylate

These compounds were prepared using procedures analogous to those forexample 11. Ms (ESI): (M+H)⁺=445.2.

Example 71(3S)-tetrahydrofuran-3-yl(2S,3S)-2-{[4-(4-tert-butylphenyl)piperazin-1-yl]carbonyl}-3-[(hydroxyamino)carbonyl]piperidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 42. Ms (ESI): (M+H)⁺=503.3.

Example 72(1R,3S,4S)-3-[(Hydroxyamino)carbonyl]-4-{[(3R)-3-phenylpyrrolidin-1-yl]carbonyl}cyclohexylpyrrolidine-1-carboxylate

To a solution of5-oxo-(2S)-[(3R)-phenyl-pyrrolidine-1-carbonyl]-cycloheane-(1S)-carboxylicacid benzyl ester (94 mg) in THF (2 mL) at −78° C. was added a solutionof L-Selectride in THF (1.5 mL, 1.0M). The solution was stirred at −78°C. for 30 min, then poured into ice-water, extracted with ethyl acetate(30 mL×2). The combined organic phases were dried with MgSO₄. Afterremoval of the solvent under reduced pressure, the residue was subjectedto HPLC analysis and found to be a mixture of two isomers in a 1:15ratio. Chromatography on silica gel afforded the major isomer at 90%yield, which was found to be the axial-hydroxy isomer. MS (ESI): 408.1(M+H⁺)

Starting from the pure axial-hydroxy compound, The titled compound wasprepared using procedures analogous to those for example 37. Ms (ESI):(M+H)⁺=430.2.

Example 73(1R,3S,4S)-3-[(Hydroxyamino)carbonyl]-4-{[(3R)-3-phenylpyrrolidin-1-yl]carbonyl}cyclohexylmorpholine-4-carboxylate

This compound was prepared using procedures analogous to those forexample 72. Ms (ESI): (M+H)⁺=446.2.

Example 74(1R,3S,4S)-3-[(Hydroxyamino)carbonyl]-4-{[(3R)-3-phenylpyrrolidin-1-yl]carbonyl}cyclohexyldimethylcarbamate

This compound was prepared using procedures analogous to those forexample 72. Ms (ESI): (M+H)⁺=404.2.

Example 75(1R,3S,4S)-3-[(Hydroxyamino)carbonyl]-4-{[(3R)-3-phenylpyrrolidin-1-yl]carbonyl}cyclohexylmethylcarbamate

This compound was prepared using procedures analogous to those forexample 72. Ms (ESI): (M+H)⁺=390.2.

Example 76((1R,3S,4S)-3-[(Hydoxyamino)carbonyl]-4-{[(3R)-3-phenylpyrrolidin-1-yl]carbonyl}cyclohexyl)carbamatePart 1

(4S)-Hydroxy-cyclohexane-(1S,2S)-dicarboxylic acid 2-benzyl ester1-tert-butyl ester (320 mg) was dissolved in DCM (5 ml). To theresulting solution was added triethylamine (1.5 eq. 0.20 ml) at rt,followed by methanesulfonyl chloride (1.55 eq. 0.115 ml), and DMAP (0.12eq. 14 mg). The mixture was stirred at r.t. for 3 hours. The reactionmixture was quenched with saturated NH₄Cl solution, extracted with ethylacetate (×2). The combined extracts were washed with water, brinesuccessively, dried over MgSO₄. After filtration, the filtrate wasconcentrated under reduced pressure to yield an oil which was furtherpurified by combi-flash. Quantitative product (400 mg) was obtained.

Part 2

The mesylate compound made above (390 mg) was dissolved in DMF (8.0 ml).To the solution, NaN₃ (10 eq., 615 mg) was added. The mixture was heatedat 80° C. with stirring over night. After cooling, the reaction wasquenched with saturated NaHCO₃ solution, extracted with ethyl acetate(×2). The combined extracts were washed with water (×1), brine (×1),dried over MgSO4. After filtration, the filtrate was concentrated underreduced pressure. The resulting residue was purified with combi-flash toafford 330 mg (95%) of azide product

Part 3

The azide compound (320 mg) was stirred with DCM (2 ml)-TFA (2 ml)solution at r.t. for 1.5 hours. The mixture was concentrated to dry toyield quantitative of the corresponding acid.

Part 4

The acid made above (100 mg) was dissolved in DMF (1 ml). To thesolution, (R)-3-phenylpyrrolidine hydrochloride (67 mg) was added,followed by BOP (153 mg). After stirring at r.t. for 5 min, to themixture was added DIEA (0.144 ml). The resultant reaction mixture wasstirred at r.t. for 4 hours. The reaction was quenched with saturatedKH₂PO₄ solution, extracted with ethyl acetate (×2). The combinedextracts were washed with water (×1), brine (×1); dried over MgSO₄.After filtration, the filtrate was concentrated under reduced pressure.The resulting residue was purified by combi-flash to yield 80 mg (56%)of(5R)-azido-(2S)-[(3R)-phenyl-pyrrolidine-1-carbonyl]-cyclohexane-(1S)-carboxylicacid benzyl ester.

Part 5

The azido compound (80 mg) was dissolved in a mixture of methanol (5 ml)and conc. HCl (0.1 mL) solution. After the addition of 10% Pd on carbon,the mixture was stirred at r.t. under hydrogen atmosphere for 2 hours.The reaction mixture was filtrated, and concentration under reducedpressure to give the corresponding amino acid in quantitative yield (60mg).

Part 6

A mixture of the amino acid made above (21 mg), methyl chloroformate(6.2 mg), and DIEA (26 ul) in acetonitrile (0.4 ml) was stirred at r.t.overnight. The reaction was quenched with 1 N HCl solution, extractedwith ethyl acetate. The combined organic phases were washed with brine(×1), dried over MgSO₄. After filtration, the filtrate was concentratedunder reduced pressure to provide(5R)-Methoxycarbonylamino-(2S)-[(3R)-phenyl-pyrrolidine-1-carbonyl]-cyclohexane-(1S)-carboxylicacid methyl ester.

Part 7

The crude methyl ester was stirred with LiOH in THF-water over night.The reaction was acidified with 1 N HCl solution, extracted with ethylacetate. The combined organic layers were washed with brine (×1), driedover MgSO₄. After filtration, the filtrate was concentrated underreduced pressure to afford 14 mg (62% in 2 step) of the correspondingacid.

Part 8

A mixture of the crude acid made above (14 mg), hydroxylaminehydrochloride (8 mg), BOP (18 mg) in DMF (0.2 ml) was stirred at rt for5 min. To the resultant mixture was added DIEA (26 ul). After beingstirred for 1.5 hours, the reaction mixture was subjected to HPLCpurification to generate the titled compound as a solid (3.1 mg, 21%).MS: M/Z 390.1 (M+H)⁺; 801.3 (2M+Na)⁺; 357.1 (M-NHOH)⁺.

Example 77(1S,2S,5R)-N-Hydroxy-5-[(methylsulfonyl)amino]-2-{[(3R)-3-phenylpyrrolidin-1-yl]carbonyl}cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 76. Ms (ESI): (M+H)⁺=410.1.

Example 78(1S,2S,5R)-5-(acetylamino)-N-hydroxy-2-{[(3R)-3-phenylpyrrolidin-1-yl]carbonyl}cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 76. Ms (ESI): (M+H)⁺=374.2.

Example 79(3R,4S)—N-Hydroxy-4-[(4-phenylpiperidin-1-yl)carbonyl]-1-(piperidin-1-ylcarbonyl)piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 12. Ms (ESI): (M+H)⁺=443.2.

Example 80(3R,4S)—N-Hydroxy-4-[(4-phenylpiperidin-1-yl)carbonyl]-1-(pyrrolidin-1-ylcarbonyl)piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 12. Ms (ESI): (M+H)⁺=429.2.

Example 81(5S,6S)-5-[(Hydroxyamino)carbonyl]-6-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]piperidin-3-ylpyrrolidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 11. Ms (ESI): (M+H)⁺=443.2.

Example 82(5S,6S)-5-[(Hydroxyamino)carbonyl]-6-[(4-phenylpiperidin-1-yl)carbonyl]piperidin-3-ylpyrrolidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 11. Ms (ESI): (M+H)⁺=445.5.

Example 83(1S,2S,5R)—N-Hydroxy-2-{[4-(3-isopropylphenyl)piperidin-1-yl]carbonyl}-5-(2-oxo-2-piperidin-1-ylethyl)cyclohexanecarboxamideand(1S,2S,5S)—N-Hydroxy-2-{[4-(3-isopropylphenyl)piperidin-1-yl]carbonyl}-5-(2-oxo-2-piperidin-1-ylethyl)cyclohexanecarboxamide

These compounds were prepared using procedures analogous to those forexample 50. Ms (ESI): (M+H)⁺=498.3.

Example 84(2S,3S)—N-Hydroxy-5-(2-oxo-2-piperidin-1-ylethyl)-2-{[(3R)-3-phenylpyrrolidin-1-yl]carbonyl}piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 2. Ms (ESI): (M+H)⁺=443.3.

Example 85(2S,3S,5R)—N-Hydroxy-5-(2-oxo-2-pyrrolidin-1-ylethyl)-2-{[(3R)-3-phenylpyrrolidin-1-yl]carbonyl}piperidine-3-carboxamideand(2S,3S,5S)—N-Hydroxy-5-(2-oxo-2-pyrrolidin-1-ylethyl)-2-{[(3R)-3-phenylpyrrolidin-1-yl]carbonyl}piperidine-3-carboxamide

These compounds were prepared using procedures analogous to those forexample 2. Ms (ESI): (M+H)⁺=429.3.

Example 86(2S,3S)—N-Hydroxy-5-(2-oxo-2-pyrrolidin-1-ylethyl)-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 2. Ms (ESI): (M+H)⁺=444.0.

Example 87(2S,3S)—N-Hydroxy-5-(2-oxo-2-piperidin-1-ylethyl)-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 2. Ms (ESI): (M+H)⁺=458.2.

Example 88(2S,3S)—N-Hydrooxy-1-methyl-5-(2-oxo-2-piperidin-1-ylethyl)-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 2. Ms (ESI): (M+H)⁺=472.1.

Example 89(2S,3S)—N-Hydroxy-1-methyl-5-(2-oxo-2-pyrrolidin-1-ylethyl)-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 2. Ms (ESI): (M+H)⁺=458.2.

Example 90(2S,3S)—N-Hydroxy-1-methyl-5-(2-oxo-2-piperidin-1-ylethyl)-2-{[(3R)-3-phenylpyrrolidin-1-yl]carbonyl}piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 2. Ms (ESI): (M+H)⁺=457.1.

Example 91(2S,3S)—N-Hydroxy-1-methyl-5-(2-oxo-2-pyrrolidin-1-ylethyl)-2-{[(3R)-3-phenylpyrrolidin-1-yl]carbonyl}piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 2. Ms (ESI): (M+H)⁺=443.0.

Example 92 Stereoselective synthesis of(1S,2S,5R)—N-Hydroxy-5-(2-oxo-2-piperidin-1-ylethyl)-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxamide

To an oven-dried 25 mL round bottomed flask equipped with a magneticstir bar and under a nitrogen gas atmosphere was placed sequentially:(S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthylbenzylbromide (12.5mg, 0.0201 mmol), rhodium (I) 1,5-cyclooctadiene chloride dimer (9.5 mg,0.019 mmol), and deoxygenated anhydrous methanol (5 mL). After stirringthe resulting yellow solution for 1 h, a solution of4-methoxycarbonylmethylidene-cyclohexane-1-(S)-2-(S)-dicarboxylic acid2-(S)-benzyl ester 1-(S)-tert-butyl ester (135 mg, 0.348 mmol) indeoxygenated anhydrous methanol (3 mL) was added via cannula. Thereaction mixture was then purged with hydrogen gas and stirred under ahydrogen balloon atmosphere for 3 d. The volatiles were then removedfrom the heterogeneous mixture in-vacuo to afford a yellow solid. TheLCMS data suggested that the starting material had been completelyconsumed and that a 30:70 mixture of the desired product and thedebenzylated desired product was formed. For the desired product LCMS(ESI): 413 (M+Na⁺), 335 (M−t-Bu+2H⁺), 803 (dimer+Na⁺). For thedebenzylated desired product LCMS (ESI): 323 (M+Na⁺), 227 (M−Ot-Bu), 153(M−Ot-Bu, CO₂H, OMe, +2H⁺), 623 (dimer+Na⁺).

Without further purification or analysis, anhydrous acetonitrile (1 mL)was added to the flask and upon vigorous stirring a hetereogeneousmixture was formed. The suspended dark solid was assumed to be inorganicbyproduct. To this solution was added 1,8-diazabicyclo[5.4.0]undec-7-ene(50 μL, 0.33 mmol) and benzylbromide (50 μL, 0.41 mmol). The resultingsolution was stirred under a nitrogen gas atmosphere for 13 h. Theheterogeneous mixture was filtered through a pad of celite, which wassubsequently washed with ethyl actetate (3×5 mL). The filtrate was thenwashed sequentially with 5% citric acid (2×3 mL), water (1×3 mL), brine(2×3 mL), dried (Na₂SO₄), and concentrated in-vacuo. Purification byCombiflash (0 to 60% ethyl acetate in hexanes over 30 min) afforded 91mg (67%) of pure product and 10 mg (7%) of the pure minor isomer. LCMS(ESI): 413 (M+Na⁺), 335 (M-t-Bu+2H⁺), 803 (dimer+Na⁺). Chiral HPLCanalysis of the isomers confirmed the optical purity and the followingNMR experiments were conducted to elucidate the absolute stereochemistryat C4 of the major isomer: ¹H, COSY, HSQC, HMBC, and NOE.

The remainder of the synthesis of5-(2-oxo-2-piperazin-1-yl-ethyl)-2-(S)-(4-phenyl-piperazine-1-carbonyl-cyclohexan-(S)-carboxylicacid hydroxyamide followed the general procedure outlined in the abovesynthesis of the racemic compound (Example 50).

Example 93(2S,3S)—N-Hydroxy-5-[isobutyryl(methyl)amino]-2-{[(3R)-3-phenylpyrrolidin-1-yl]carbonyl}piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 6. Ms (ESI): (M+H)⁺=417.2.

Example 94(2S,3S)—N-Hydroxy-5-[isobutyryl(methyl)amino]-2-[(3-phenyl-2,5-dihydro-1H-pyrrol-1-yl)carbonyl]piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 6. Ms (ESI): (M+H)⁺=415.2.

Example 95(2S,3S)—N-Hydroxy-5-[isobutyryl(methyl)amino]-2-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 6. Ms (ESI): (M+H)⁺=429.2.

Example 96(2S,3S)—N-Hydroxy-5-[isobutyryl(methyl)amino]-2-[(4-phenylpiperidin-1-yl)carbonyl]piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 6. Ms (ESI): (M+H)⁺=431.3.

Example 97(2S,3S)—N-Hydroxy-5-[isobutyryl(methyl)amino]-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 6. Ms (ESI): (M+H)⁺=432.3.

Example 98(3R,4S)—N-Hydroxy-4-{[(3S)-3-phenylpyrrolidin-1-yl]carbonyl}-1-[4-(trifluoromethoxy)benzoyl]piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 12. Ms (ESI): (M+H)⁺=506.2.

Example 99(3R,4S)—N-Hydroxy-4-{[(3S)-3-phenylpyrrolidin-1-yl]carbonyl}-1-{[4-(trifluoromethoxy)phenyl]sulfonyl}piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 12. Ms (ESI): (M+H)⁺=542.0.

Example 100(3R,4S)—N-Hydroxy-4-{[(3S)-3-phenylpyrrolidin-1-yl]carbonyl}-1-[3-(trifluoromethoxy)benzoyl]piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 12. Ms (ESI): (M+H)⁺=506.2.

Example 101(3R,4S)—N-Hydroxy-4-{[(3S)-3-phenylpyrrolidin-1-yl]carbonyl}-1-[2-(trifluoromethoxy)benzoyl]piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 12. Ms (ESI): (M+H)⁺=506.0.

Example 102(3R,4S)—N-Hydroxy-1-[4-(difluoromethoxy)benzoyl]-4-{[(3S)-3-phenylpyrrolidin-1-yl]carbonyl}piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 12. Ms (ESI): (M+H)⁺=488.2.

Example 103(5S,6S)-5-[(Hydroxyamino)carbonyl]-6-{[(3S)-3-phenylpyrrolidin-1-yl]carbonyl}piperidin-3-ylpyrrolidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 11. Ms (ESI): (M+H)⁺=431.2.

Example 104(5S,6S)-5-[(Hydroxyamino)carbonyl]-6-[(4-phenylpiperazin-1-yl)carbonyl]piperidin-3-ylpyrrolidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 11. Ms (ESI): (M+H)⁺=446.2.

Example 105(5S,6S)-5-[(Hydroxyamino)carbonyl]-6-[(3-phenyl-2,5-dihydro-1H-pyrrol-1-yl)carbonyl]piperidin-3-ylpyrrolidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 11. Ms (ESI): (M+H)⁺=429.2.

Example 106methyl(2S,3S)-3-[(Hydroxyamino)carbonyl]-2-[(3-phenyl-2,5-dihydro-1H-pyrrol-1-yl)carbonyl]-5-[(pyrrolidin-1-ylcarbonyl)oxy]piperidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 11. Ms (ESI): (M+H)⁺=487.2.

Example 107methyl(2S,3S)-3-[(hydroxyamino)carbonyl]-2-{[(3S)-3-phenylpyrrolidin-1-yl]carbonyl}-5-[(pyrrolidin-1-ylcarbonyl)oxy]piperidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 11. Ms (ESI): (M+H)⁺=489.2.

Example 108Methyl(2S,3S)-3-[(hydroxyamino)carbonyl]-2-[(4-phenylpiperidin-1-yl)carbonyl]-5-[(pyrrolidin-1-ylcarbonyl)oxy]piperidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 11. Ms (ESI): (M+H)⁺=503.3.

Example 109Methyl(2S,3S)-3-[(hydroxyamino)carbonyl]-2-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]-5-[(pyrrolidin-1-ylcarbonyl)oxy]piperidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 11. Ms (ESI): (M+H)⁺=501.2.

Example 110Methyl(2S,3S)-3-[(hydroxyamino)carbonyl]-2-[(4-phenylpiperazin-1-yl)carbonyl]-5-[(pyrrolidin-1-ylcarbonyl)oxy]piperidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 11. Ms (ESI): (M+H)⁺=504.3.

Example 111(2S,3S)-5-[benzoyl(methyl)amino]-N-hydroxy-2-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 6. Ms (ESI): (M+H)⁺=463.2.

Example 112(2S,3S)-5-[benzoyl(methyl)amino]-N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 6. Ms (ESI): (M+H)⁺=466.2.

Example 113 isopropyl{(5S,6S)-5-[(hydroxyamino)carbonyl]-6-[(4-phenylpiperazin-1-yl)carbonyl]piperidin-3-yl}methylcarbamate

This compound was prepared using procedures analogous to those forexample 6. Ms (ESI): (M+H)⁺=448.3.

Example 114 isopropyl{(5S,6S)-5-[(hydroxyamino)carbonyl]-6-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]piperidin-3-yl}methylcarbamate

This compound was prepared using procedures analogous to those forexample 6. Ms (ESI): (M+H)⁺=445.2.

(1S,2S,5R)-N,5-dihydroxy-2-{[(3R)-3-phenylpyrrolidin-1-yl]carbonyl}-5-propylcyclohexanecarboxamideand(1S,2S,5S)—N,5-dihydroxy-2-{[(3R)-3-phenylpyrrolidin-1-yl]carbonyl}-5-propylcyclohexanecarboxamide

To a solution of5-oxo-(2S)-[(3R)-phenyl-pyrrolidine-1-carbonyl]-cycloheane-(1S)-carboxylicacid benzyl ester (120 mg, 0.296 mMol) in methylene chloride at 0° C.was added allyltrimethyl silane (0.94 mL) followed by titaniumtetrachloride (1.48 mL, 1.0 M in CH₂Cl₂) dropwise. After being stirredat 0° C. for about 20 minutes, the mixture was allowed to warm up toroom temperature and stirred at rt for about 3 hours. The reaction waspoured into ice-water and extracted with ethyl acetate. The combinedorganic phases were washed with water, brine, and then dried with MgSO₄.After filtration, the filtrate was concentrated under reduced pressure.The residue was purified with Combiflash using 7% methanol in methylenechloride to afford5-Hydroxy-(2S)-[(3R)-phenyl-pyrrolidine-1-carbonyl]-5-propyl-cyclohexane-(1S)-carboxylicacid benzyl ester as a diastereoisomer mixtures (48 mg, 37%).

The remainder of the synthesis(5R)-5-Hydroxy-(2S)-[(3R)-phenyl-pyrrolidine-1-carbonyl]-5-propyl-cyclohexane-(1S)-carboxylicacid hydroxyamide and(5S)-5-Hydroxy-(2S)-[(3R)-phenyl-pyrrolidine-1-carbonyl]-5-propyl-cyclohexane-(1S)-carboxylicacid hydroxyamide followed the general procedure outlined in Example 25.The two isomers were separated by HPLC at the final step. Ms (ESI):(M+H)⁺=375.2.

Example 116(1S,3S,4S)-4-{[4-(4-tert-butylphenyl)piperazin-1-yl]carbonyl}-3-[(hydroxyamino)carbonyl]cyclohexylmethylcarbamate

This compound was prepared using procedures analogous to those forexample 37. Ms (ESI): (M+H)⁺=461.3.

Example 117(1S,3S,4S)-4-{[4-(4-tert-butylphenyl)piperazin-1-yl]carbonyl}-3-[(hydroxyamino)carbonyl]cyclohexyldimethylcarbamate

This compound was prepared using procedures analogous to those forexample 37. Ms (ESI): (M+H)⁺=475.3.

Example 118(1S,3S,4S)-4-{[4-(4-tert-butylphenyl)piperazin-1-yl]carbonyl}-3-[(hydroxyamino)carbonyl]cyclohexylcyclopropylcarbamate

This compound was prepared using procedures analogous to those forexample 37. Ms (ESI): (M+H)⁺=487.3.

Example 119(1S,3S,4S)-4-{[4-(4-tert-butylphenyl)piperazin-1-yl]carbonyl}-3-[(hydroxyamino)carbonyl]cyclohexylpyrrolidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 37. Ms (ESI): (M+H)⁺=501.3.

Example 120(1S,3S,4S)-4-{[4-(4-tert-butylphenyl)piperazin-1-yl]carbonyl}-3-[(hydroxyamino)carbonyl]cyclohexyl(3R)-3-hydroxypyrrolidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 37. Ms (ESI): (M+H)⁺=517.3.

Example 121(1S,3S,4S)-4-{[4-(4-tert-butylphenyl)piperazin-1-yl]carbonyl}-3-[(hydroxyamino)carbonyl]cyclohexylmorpholine-4-carboxylate

This compound was prepared using procedures analogous to those forexample 37. Ms (ESI): (M+H)⁺=517.3.

Example 122(1S,3S,4S)-4-{[4-(4-tert-butylphenyl)piperazin-1-yl]carbonyl}-3-[(hydroxyamino)carbonyl]cyclohexylpiperidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 37. Ms (ESI): (M+H)⁺=515.3.

Example 123(1R,3S,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]cyclohexylmethylcarbamate

This compound was prepared using procedures analogous to those forexample 72. Ms (ESI): (M+H⁺)=402.1

Example 124(1R,3S,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]cyclohexyldimethylcarbamate

This compound was prepared using procedures analogous to those forexample 72. Ms (ESI): (M+H⁺)=416.1

Example 125(1R,3S,4S)-3-[(Hydroxyamino)carbonyl]-4-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]cyclohexylpyrrolidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 72. Ms (ESI): (M+H⁺)=442.1.

Example 126methyl(2S,3S,5S)-5-(3-fluorophenoxy)-3-[(hydroxyamino)carbonyl]-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1-carboxylatePart 1. (S)-2-Benzylamino-succinic acid 1-benzyl ester 4-methyl ester

To a suspension of L-Aspartic acid β-methyl ester HCl salt (50.00 g,0.2704 mol) in acetonitrile (500.00 mL, 9.5732 mol) was added1,8-diazabicyclo[5.4.0]undec-7-ene (124 mL, 0.811 mol) at 0 Celsius,followed by benzyl bromide (65.6 mL, 0.541 mol) at one portion. Thereaction mixture was allowed to warm up to rt and stirred at rtovernight. The resultant mixture was concentrated to almost dry, dilutedwith EtOAc, then filtered through Celite to remove the DBU HCl salt. Thefiltration was concentrated under reduced pressure. The residue wasapplied on silica gel chromatography, eluting with 0 to 20% EtOAc inhexane to afford the desired product (30.20 g, 34.1%).

Part 2. 1-benzyl4-methyl(2S)-2-[benzyl((2S)-2-hydroxy-3-[(4-methylphenyl)sulfonyl]oxypropyl)amino]succinate

To a solution of (2S)-(+)-glycidyl tosylate (23.0 g, 0.101 mol) in 500mL of methylene chloride was added 2.00 M of trimethylaluminum intoluene (50.4 mL) at −78 Celsius, under an atmosphere of nitrogen. Afterstirred at −78 Celsius for 10 min, to the mixture was added a solutionof (S)-2-benzylamino-succinic acid 1-benzyl ester 4-methyl ester (30.0g, 0.0916 mol) in 150 mL of methylene chloride. The resulting reactionmixture was stirred at −78 Celsius for 30 min. The dry ice-acetone bathwas changed to an ice-water bath to warm the mixture up to 0 Celsius.The mixture was stirred at 0 Celsius for 30 min. To the reaction mixturewas added sodium fluoride (16.2 g, 0.385 mol) followed by water (10.4mL, 0.577 mol) at 0 Celsius. The resulting suspension was rapidlystirred for 1 h at 0 Celsius and filtered through a short column of ofcelite and the column was subsequently washed with 600 mL of methylenechloride. The combined filtrates were dried over sodium sulfate,concentrated to dry and purified by column purification (eluting with 0to 20% EtOAc in hexane) to yield The titled compound (46.7 g, 91.7%). MS(ESI): (M+H)⁺=556.2.

Part 3. 1-benzyl4-methyl(2S)-2-[benzyl((2S)-2-(1-ethoxyethoxy)-3-[(4-methylphenyl)sulfony]oxypropyl)amino]succinate

To a mixture of 1-benzyl4-methyl(2S)-2-[benzyl((2S)-2-hydroxy-3-[(4-methylphenyl)sulfonyl]oxypropyl)amino]succinate(43.0 g, 0.0774 mol) in methylene chloride (600.0 mL, 9.360 mol) wasadded ethyl vinyl ether (14.8 mL, 0.155 mol) followed by pyridiniump-toluenesulfonate (1 g, 0.004 mol). The mixture was stirred at rt for 1h, concentrated to dry and purified on silical gel (eluting with 0 to20% EtOAc in hexane) to afford the ether compound (39.7 g, 81.7%). MS(ESI): (M+H)⁺=628.1.

Part 4. 2-benzyl3-methyl(2S,3S,5R)-1-benzyl-5-(1-ethoxyethoxy)piperidine-2,3-dicarboxylate

To a solution of 1-benzyl4-methyl(2S)-2-[benzyl((2S)-2-(1-ethoxyethoxy)-3-[(4-methylphenyl)sulfonyl]oxypropyl)amino]succinate(35.7 g, 0.0569 mol) in a mixture of tetrahydrofuran (95.5 mL, 1.18 mol)and toluene (490 mL, 4.6 mol) at −78 Celsius was was added 1.00 M ofLithium hexamethyldisilazide in tetrahydrofuran (68.2 mL). The reactionwas stirred at −78 Celsius overnight then allowed to warm up to −20Celsius and stirred at −20 Celsius for 3 h. After quenched with aqammonium chloride, the mixture was extracted with ethyl acetate. Thecombined organic layers were washed with brine, dried and concentratedto dry. The residue was applied on silica gel column, eluting with 0 to20% EtOAc in hexane, to afford the product (18.1 g, 69.9%). MS (ESI):(M+H)⁺=456.2. The corresponding diastereoisomer was also obtained (4.52g, 17.5%).

Part 5. 2-benzyl3-methyl(2S,3S,5R)-1-benzyl-5-hydroxypiperidine-2,3-dicarboxylate

To a solution of 2-benzyl3-methyl(2S,3S,5R)-1-benzyl-5-(1-ethoxyethoxy)piperidine-2,3-dicarboxylate(5.70 g, 0.0125 mol) in 100 mL of THF was added 20 mL of water followedby 20 mL of 1N HCl. The mixture was stirred at rt fro 1 h. After dilutedwith EtOAc, the mixture was neutralized with 1N NaOH, washed with brine,dried. The residue obtained after concentration was applied on silical,eluting with 0 to 50% EtOAc in hexane, to provide the alcohol compound(4.80 g, 89.6%). MS (ESI): (M+H)⁺=384.2.

Part 6. (2S,3S,5R)-5-hydroxy-3-(methoxycarbonyl)piperidine-2-carboxylicacid

A mixture of 2-benzyl3-methyl(2S,3S,5R)-1-benzyl-5-hydroxypiperidine-2,3-dicarboxylate (1.00g, 0.00261 mol) in 10 mL of methanol was hydrogenated in the presence of10% Pd/C, under a balloon pressure of hydrogen, for 3 h. After filteredoff the catalyst, the filtration was concentrated to dry in vacuo andused directly in next step. MS (ESI): (M+H)⁺=204.0.

Part 7.dimethyl(2S,3S,5R)-5-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1,3-dicarboxylate

To a mixture of(2S,3S,5R)-5-hydroxy-3-(methoxycarbonyl)piperidine-2-carboxylic acid(3.140 g, 0.01545 mol), 1-phenyl-piperazine (2.597 mL, 0.01700 mol) andbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(7.518 g, 0.01700 mol) in N,N-dimethylformamide (10.00 mL, 0.1291 mol)was added N,N-diisopropylethylamine (3.230 mL, 0.01854 mol) at 0Celsius. After stirred at rt overnight. the reaction mixture was dilutedwith methylene chloride (90.0 mL, 1.40 mol) and then cooled to 0Celsius. To the mixture was added N,N-diisopropylethylamine (5.38 mL,0.0309 mol) followed by methyl chloroformate (2.39 mL, 0.0309 mol). Themixture was stirred at rt for 2 h and then concentrated to dry. Theresidue was diluted with water and extracted with ethyl acetate. Thecombined organic layers were washed with brine, dried and concentratedto dry. The residue was purified on silica gel, eluting with 0 to 100%EtOAc in hexane, to give The titled compound (5.20 g, 83.0%). MS (ESI):(M+H)⁺=406.1.

Part 8.dimethyl(2S,3S,5S)-5-(3-fluorophenoxy)-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1,3-dicarboxylate

To a solution ofdimethyl(2S,3S,5R)-5-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1,3-dicarboxylate(50.0 mg, 0.000123 mol) in tetrahydrofuran (0.50 mL, 0.00617 mol) wasadded 3-fluoro-phenol (0.0134 mL, 0.000148 mol), triphenylphosphine(38.8 mg, 0.000148 mol), followed by diethyl azodicarboxylate (0.0233mL, 0.000148 mol). The mixture was heated at 70 Celsius overnight. Afterconcentrated to dry, the mixture was purified on silica gel, elutingwith 0 to 40% EtOAc in hexane, to generate the phenyl ether compound (27mg, 44%). MS (ESI): (M+H)⁺=500.05.

Part 9.methyl(2S,3S,5S)-5-(3-fluorophenoxy)-3-[(hydroxyamino)carbonyl]-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1-carboxylate

To a solution ofdimethyl(2S,3S,5S)-5-(3-fluorophenoxy)-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1,3-dicarboxylate(27 mg, 0.000054 mol) in methanol (0.2189 mL, 0.005405 mol) was added1.640 M of N-hydroxyamine in Methanol (0.659 mL) made from thecorresponding HCl salt and sodium methoxide. After stirred at rt for 1h, the mixture was acidified with 1N HCl. The resultant mixture wasapplied directly on RP-HPLC to afford the product as a TFA salt (18 mg54.5%). MS (ESI): (M+H)⁺=501.2.

Example 127methyl(2S,3S,5S)-3-[(hydroxyamino)carbonyl]-2-[(4-phenylpiperazin-1-yl)carbonyl]-5-[3-(trifluoromethyl)phenoxy]piperidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 126. MS (ESI): (M+H)⁺=551.1.

Example 128methyl(2S,3S,5S)-5-(2,4-difluorophenoxy)-3-[(hydroxyamino)carbonyl]-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 126. MS (ESI): (M+H)⁺=519.0.

Example 129methyl(2S,3S,5S)-5-(3-chloro-4-fluorophenoxy)-3-[(hydroxyamino)carbonyl]-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 126. MS (ESI): (M+H)⁺=535.0.

Example 130methyl(2S,3S,5S)-5-[(5-chloropyridin-3-yl)oxy]-3-[(hydroxyamino)carbonyl]-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 126. MS (ESI): (M+H)⁺=518.1.

Example 131methyl(2S,3S,5S)-5-(3-bromophenoxy)-3-[(hydroxyamino)carbonyl]-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 126. MS (ESI): (M+H)⁺=561.0.

Example 132methyl(2S,3S,5S)-3-[(hydroxyamino)carbonyl]-2-[(4-phenylpiperazin-1-yl)carbonyl]-5-(pyridin-3-yloxy)piperidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 126. MS (ESI): (M+H)⁺=484.1.

Example 133methyl(2S,3S,5S)-3-[(hydroxyamino)carbonyl]-2-[(4-phenylpiperazin-1-yl)carbonyl]-5-(quinolin-6-yloxy)piperidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 126. MS (ESI): (M+H)⁺=534.1.

Example 134methyl(2S,3S,5S)-3-[(hydroxyamino)carbonyl]-5-(3-methylphenoxy)-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 126. MS (ESI): (M+H)⁺=497.1.

Example 135methyl(2S,3S,5S)-3-[(hydroxyamino)carbonyl]-5-(3-methoxyphenoxy)-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 126. MS (ESI): (M+H)⁺=513.1.

Example 136methyl(2S,3S,5S)-3-[(hydroxyamino)carbonyl]-5-[(6-methylpyridin-2-yl)oxy]-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 126. MS (ESI): (M+H)⁺=498.1.

Example 137methyl(2S,3S,5S)-3-[(hydroxyamino)carbonyl]-5-[(2-methylquinolin-4-yl)oxy]-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 126. MS (ESI): (M+H)⁺=548.15.

Example 138methyl(2S,3S,5S)-3-[(hydroxyamino)carbonyl]-5-phenoxy-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 126. MS (ESI): (M+H)⁺=483.2.

Example 139methyl(2S,3S,5S)-5-(3-chlorophenoxy)-3-[(hydroxyamino)carbonyl]-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 126. MS (ESI): (M+H)⁺=517.0.

Example 140methyl(2S,3S,5S)-5-(2,3-difluorophenoxy)-3-[(hydroxyamino)carbonyl]-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 126. MS (ESI): (M+H)⁺=519.1.

Example 141methyl(2S,3S,5S)-3-[(hydroxyamino)carbonyl]-2-[(4-phenylpiperazin-1-yl)carbonyl]-5-(pyridin-2-yloxy)piperidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 126. MS (ESI): (M+H)⁺=484.1.

Example 142methyl(2S,3S,5S)-3-[(hydroxyamino)carbonyl]-2-[(4-phenylpiperazin-1-yl)carbonyl]-5-(quinolin-4-yloxy)piperidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 126. MS (ESI): (M+H)⁺=534.1.

Example 143methyl(2S,3S,5S)-3-[(hydroxyamino)carbonyl]-2-[(4-phenylpiperazin-1-yl)carbonyl]-5-(pyridin-4-yloxy)piperidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 126. MS (ESI): (M+H)⁺=484.05.

Example 144methyl(2S,3S,5S)-3-[(hydroxyamino)carbonyl]-5-[(4-methylpyridin-2-yl)oxy]-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 126. MS (ESI): (M+H)⁺=498.2.

Example 145methyl(2S,3S,5S)-5-(2-fluorophenoxy)-3-[(hydroxyamino)carbonyl]-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 126. MS (ESI): (M+H)⁺=501.1.

Example 146methyl(2S,3S,5S)-3-[(hydroxyamino)carbonyl]-5-(2-methylphenoxy)-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 126. MS (ESI): (M+H)⁺=497.1.

Example 147methyl(2S,3S,5S)-5-(4-fluorophenoxy)-3-[(hydroxyamino)carbonyl]-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 126. MS (ESI): (M+H)⁺=501.1.

Example 148methyl(2S,3S,5S)-5-(3,5-difluorophenoxy)-3-[(hydroxyamino)carbonyl]-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 126. MS (ESI): (M+H)⁺=519.0.

Example 150methyl(2S,3S,5S)-5-(1,3-benzothiazol-2-yloxy)-3-[(hydroxyamino)carbonyl]-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 126. MS (ESI): (M+H)⁺=540.1.

Example 151methyl(2S,3S,5S)-5-(3,4-difluorophenoxy)-3-[(hydroxyamino)carbonyl]-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 126. MS (ESI): (M+H)⁺=519.0.

Example 152(2S,3S,5S)—N-hydroxy-1-methyl-2-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]-5-(pyridin-4-yloxy)piperidine-3-carboxamidePart 1. 1-tert-butyl3-methyl(2S,3S,5R)-5-hydroxy-2-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]piperidine-1,3-dicarboxylate

A mixture of(2S,3S,5R)-5-hydroxy-3-(methoxycarbonyl)piperidine-2-carboxylic acid(1.851 g, 0.009110 mol), 4-phenyl-1,2,3,6-tetrahydropyridinehydrochloride (2.14 g, 0.0109 mol) andbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(4.83 g, 0.0109 mol) in N,N-dimethylformamide (15.0 mL, 0.194 mol) wasstirred at rt for 5 min, then treated with N,N-diisopropylethylamine(3.81 mL, 0.0219 mol) at rt for 2 h. The reaction mixture was dilutedwith methylene chloride (10.0 mL, 0.156 mol). The resultant mixture wasthen treated with N,N-diisopropylethylamine (3.17 mL, 0.0182 mol),followed by di-tert-butyldicarbonate (3.98 g, 0.0182 mol) at rtovernight. The reaction was diluted with water, extracted with EtOAc.The combined orgnica layers were washed with brine, dried, andconcentrated to dry in vacuo. The residue was applied on silica gel,eluting with 0 to 80% EtOAc in hexane, to give The titled compound (2.10g, 51.9%). MS (ESI): (M+H-Boc)⁺=345.1.

Part 2. 1-tert-butyl3-methyl(2S,3S,5S)-2-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]-5-(pyridin-4-yloxy)piperidine-1,3-dicarboxylate

To a solution of 1-tert-butyl3-methyl(2S,3S,5R)-5-hydroxy-2-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]piperidine-1,3-dicarboxylate(100 mg, 0.0002 mol) in tetrahydrofuran (0.912 mL, 0.0112 mol) was added4-pyridinol (25.7 mg, 0.000270 mol), triphenylphosphine (70.8 mg,0.000270 mol), followed by diisopropyl azodicarboxylate (0.0532 mL,0.000270 mol). The mixture was heated at 70 Celsius overnight. Afterconcentrated to dry, the mixture was purified on silica gel, elutingwith 0 to 40% EtOAc in hexane, to afford the desired ether compound (56mg, 50%). MS (ESI): (M+H)⁺=522.1.

Part 3.methyl(2S,3S,5S)-1-methyl-2-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]-5-(pyridin-4-yloxy)piperidine-3-carboxylate

1-tert-butyl3-methyl(2S,3S,5S)-2-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]-5-(pyridin-4-yloxy)piperidine-1,3-dicarboxylate(0.09 g, 0.0002 mol) was treated with trifluoroacetic acid (1.0 mL,0.013 mol) at rt for 1 h. The mixture was then concentrated to dry. Thecrude secondary amine made above was dissolved in tetrahydrofuran (0.80mL, 0.0099 mol) and acetonitrile (0.80 mL, 0.015 mol). The mixture wasthen treated with N,N-diisopropylethylamine (0.061 mL, 0.00035 mol) toadjust the pH to around 7. To the resultant mixture was then added 12.32M of formaldehyde in water (0.071 mL) followed by sodiumtriacetoxyborohydride (180 mg, 0.00087 mol). After stirred at rtovernight, the mixture was concentrated to dry in vacuo, diluted withwith aq. sodium bicarbonate, extracted with EtOAc. The combined organiclayers were washed with brine, dried, and evaporated to dry in vacuo.The residue was exposured in high vacuum and then used directly in nextstep. MS (ESI): (M+H)⁺=436.1.

Part 4.(2S,3S,5S)—N-hydroxy-1-methyl-2-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]-5-(pyridin-4-yloxy)piperidine-3-carboxamide

To a solution of methyl(2S,3S,5S)-1-methyl-2-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]-5-(pyridin-4-yloxy)piperidine-3-carboxylate(70 mg, 0.0002 mol) in methanol (0.6674 mL, 0.01648 mol) was added 1.640M of N-hydroxyamine in Methanol (2.01 mL) made from the correspondingHCl salt and sodium methoxide. After stirred at rt for 1 h, the mixturewas acidified with 1N HCl. The resultant mixture was applied directly onRP-HPLC to afford the product as a TFA salt (56 mg, 63.4%). MS (ESI):(M+H)⁺=437.1.

Example 153(2S,3S,5S)—N-hydroxy-1-methyl-5-[(4-methylpyridin-2-yl)oxy]-2-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 152. MS (ESI): (M+H)⁺=451.1.

Example 154(2S,3S,5S)—N-hydroxy-1-methyl-5-phenoxy-2-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 152. MS (ESI): (M+H)⁺=436.0.

Example 155(2S,3S,5S)-5-(3-fluorophenoxy)-N-hydroxy-1-methyl-2-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 152. MS (ESI): (M+H)⁺=454.1.

Example 156(2S,3S,5S)—N-hydroxy-1-methyl-2-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]-5-(quinolin-6-yloxy)piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 152. MS (ESI): (M+H)⁺=487.0.

Example 157(2S,3S,5S)—N-hydroxy-1-methyl-5-[(2-methylquinolin-4-yl)oxy]-2-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 152. MS (ESI): (M+H)⁺=501.1.

Example 158(2S,3S,5S)—N-hydroxy-1-methyl-2-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]-5-(pyridin-2-yloxy)piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 152. MS (ESI): (M+H)⁺=437.0.

Example 159(2S,3S,5S)-5-(3,5-difluorophenoxy)-N-hydroxy-1-methyl-2-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 152. MS (ESI): (M+H)⁺=472.1.

Example 160(2S,3S,5S)—N-hydroxy-1-methyl-2-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]-5-(quinolin-4-yloxy)piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 152. MS (ESI): (M+H)⁺=486.9.

Example 1612S,3S,5S)—N-hydroxy-1-methyl-2-[(4-phenylpiperidin-1-yl)carbonyl]-5-(pyridin-4-yloxy)piperidine-3-carboxamide(1a

A mixture of(2S,3S,5S)—N-hydroxy-1-methyl-2-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]-5-(pyridin-4-yloxy)piperidine-3-carboxamideTFA salt (4 mg, 0.00001 mol) in 1 mL of MeOH was hydrogenated in thepresence of 5% Pd/BaSO₄, under balloon pressure of hydrogen, for 2 h.After filtered off the catalyst, the filtration was concentrated to dryto yield The titled compound (4 mg, 100%). MS (ESI): (M+H)⁺=439.2.

Example 162(2S,3S,5S)—N-hydroxy-1-methyl-5-[(2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)oxy]-2-[(4-phenylpiperidin-1-yl)carbonyl]piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 161. MS (ESI): (M+H)⁺=507.2.

Example 163(2S,3S,5S)—N-hydroxy-1-methyl-5-[(4-methylpyridin-2-yl)oxy]-2-[(4-phenylpiperidin-1-yl)carbonyl]piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 161. MS (ESI): (M+H)⁺=453.0.

Example 164(2S,3S,5S)—N-hydroxy-1-methyl-2-[(4-phenylpiperidin-1-yl)carbonyl]-5-(pyridin-2-yloxy)piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 161. MS (ESI): (M+H)⁺=439.1.

Example 165(2S,3S,5S)—N-hydroxy-1-(methylsulfonyl)-5-phenoxy-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 126. MS (ESI): (M+H)⁺=503.2.

Example 166(3S)-tetrahydrofuran-3-yl(2S,3S,5S)-3-[(hydroxyamino)carbonyl]-5-phenoxy-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 126. MS (ESI): (M+H)⁺=539.2.

Example 167methyl(2S,3S,5S)-5-(2-bromophenoxy)-3-[(hydroxyamino)carbonyl]-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 126.

Example 168methyl(2S,3S,5S)-5-(2-chlorophenoxy)-3-[(hydroxyamino)carbonyl]-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 126. MS (ESI): (M+H)⁺=517.2.

Example 169tetrahydro-2H-pyran-4-yl(2S,3S,5S)-3-[(hydroxyamino)carbonyl]-5-phenoxy-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 126. MS (ESI): (M+H)⁺=553.2.

Example 170ethyl(2S,3S,5S)-3-[(hydroxyamino)carbonyl]-5-phenoxy-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 126. MS (ESI): (M+H)⁺=497.2.

Example 171(2S,3S,5S)—N-hydroxy-5-(3-methylphenoxy)-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 152. MS (ESI): (M+H)⁺=439.1.

Example 172(2S,3S,5S)—N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]-5-[3-(trifluoromethyl)phenoxy]piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 152. MS (ESI): (M+H)⁺=493.2.

Example 173(2S,3S,5S)-5-(3-chlorophenoxy)-N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 152. MS (ESI): (M+H)⁺=459.2.

Example 174(2S,3S,5S)—N-hydroxy-5-(3-methoxyphenoxy)-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 152. MS (ESI): (M+H)⁺=455.0.

Example 175(2S,3S,5S)-5-(3-fluorophenoxy)-N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 152. MS (ESI): (M+H)⁺=443.2.

Example 176(3S,5S,6S)-5-[(hydroxyamino)carbonyl]-1-methyl-6-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]piperidin-3-ylpiperidine-1-carboxylate Part 1. 1-benzyl4-methyl(2S)-2-[benzyl((2R)-2-hydroxy-3-[(4-methylphenyl)sulfonyl]oxypropyl)amino]succinate

To a solution of (2R)-oxiran-2-ylmethyl 4-methylbenzenesulfonate (23.0g, 0.101 mol) in 500 mL of methylene chloride was added 2.000 M oftrimethylaluminum in Toluene (50.4 mL) at −78 Celsius, under anatmosphere of nitrogen. After stirred at −78 Celsius for 10 min, to themixture was added a solution of (S)-2-benzylamino-succinic acid 1-benzylester 4-methyl ester (30.0 g, 0.0916 mol) in 150 mL of methylenechloride. The resulting reaction mixture was stirred at −78 Celsius for30 min. The dry ice-acetone bath was changed to an ice-water bath towarm the mixture up to 0 Celsius. The mixture was stirred at 0 Celsiusfor 30 min. To the reaction mixture was added sodium fluoride (16.2 g,0.385 mol) followed by Water (10.4 mL, 0.577 mol) at 0 Celsius. Theresulting suspension was rapidly stirred for 1 h at 0 Celsius andfiltered through a short column of of Celite and the column wassubsequently washed with 600 mL of methylene chloride. The combinedfiltrates were dried over sodium sulfate, concentrated to dry andpurified by column purification (eluting with 0 to 30% EtOAc in hexane)to give The titled compound (43.0 g, 84.4%). MS (ESI): (M+H)⁺=556.1.

Part 2. 1-benzyl4-methyl(2S)-2-[benzyl((2R)-2-(1-ethoxyethoxy)-3-[(4-methylphenyl)sulfonyl]oxypropyl)amino]succinate

To a solution of 1-benzyl4-methyl(2S)-2-[benzyl((2R)-2-hydroxy-3-[(4-methylphenyl)sulfonyl]oxypropyl)amino]succinate(43.0 g, 0.0774 mol) in methylene chloride (500.0 mL, 7.800 mol) wasadded ethyl vinyl ether (15.0 mL, 0.157 mol) followed by pyridiniump-toluenesulfonate (4.0 g, 0.016 mol). The mixture was stirred at rt for3 g. After concentrated to dry, the residue was purified by silical gelcolumn (eluting with 0 to 20% EtOAc in hexane) to provide the ethercompound (38.1 g, 78.4%). MS (ESI): (M+H)⁺=628.1.

Part 3. 2-benzyl3-methyl(2S,3S,5S)-1-benzyl-5-(1-ethoxyethoxy)piperidine-2,3-dicarboxylate

To a solution of 1-benzyl4-methyl(2S)-2-[benzyl((2R)-2-(1-ethoxyethoxy)-3-[(4-methylphenyl)sulfonyl]oxypropyl)amino]succinate(34.30 g, 0.05464 mol) in a mixture of tetrahydrofuran (90.0 mL, 1.11mol) and toluene (470.0 mL, 4.412 mol) at −78 Celsius was added 1.00 Mof Lithium hexamethyldisilazide in tetrahydrofuran (65.6 mL). Theresulting mixture was stirred at −78 Celsius overnight, and then allowedto warm up to at 0 Celsius gradually and stirred at 0 Celsius for 30min. After quenched with aq ammonium chloride, the mixture was extractedwith ethyl acetate. The combined organic layers were washed with water,brine, and dried (sodium sulfate), and concentrated to dry. The residuewas purified on silica gel column, eluting with 0 to 20% EtOAc inhexane, to yield the cyclized product (19.47 g, 78.2%). MS (ESI):(M+H)⁺=456.0.

Part 4. 2-benzyl3-methyl(2S,3S,5S)-1-benzyl-5-hydroxypiperidine-2,3-dicarboxylate

To a solution of 2-benzyl3-methyl(2S,3S,5S)-1-benzyl-5-(1-ethoxyethoxy)piperidine-2,3-dicarboxylate(3.80 g, 0.00834 mol) in 67 mL of THF was added 13 mL of water followedby 13 mL of 1 N HCl. The mixture was stirred at rt for 1 h. Afterdiluted with ethyl acetate, the mixture was neutralized with 1N NaOH,washed with brine, dried. The residue after concentration was purifiedon column, eluting with 0 to 50% EtOAc in hexane, to generate thecorresponding alcohol compound (2.90 g, 90.6%). MS (ESI): (M+H)⁺=384.1.

Part 5. (2S,3S,5S)-5-hydroxy-3-(methoxycarbonyl)piperidine-2-carboxylicacid

A solution of 2-benzyl3-methyl(2S,3S,5S)-1-benzyl-5-hydroxypiperidine-2,3-dicarboxylate (2.00g, 0.00522 mol) in 30 mL of methanol was hydrogenated in the presence of10% Pd/C, under a balloon pressure of hydrogen, overnight. Afterfiltered off the catalyst, the filtration was concentrated to dry andused directly in next step.

Part 6.methyl(2S,3S,5S)-5-hydroxy-1-methyl-2-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]piperidine-3-carboxylate

A mixture of(2S,3S,5S)-5-hydroxy-3-(methoxycarbonyl)piperidine-2-carboxylic acid(0.309 g, 0.00152 mol), 4-phenyl-1,2,3,6-tetrahydropyridinehydrochloride (0.357 g, 0.00182 mol) andbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(0.807 g, 0.00182 mol) in N,N-dimethylformamide (2.50 mL, 0.0323 mol)was stirred at rt for 5 min, then treated with N,N-diisopropylethylamine(0.636 mL, 0.00365 mol) at rt for 2 h. The reaction mixture was dilutedwith acetonitrile (5.0 mL, 0.096 mol) and tetrahydrofuran (5.0 mL, 0.062mol). To the mixture was added 12.32 M of formaldehyde in Water (0.41mL) followed by sodium triacetoxyborohydride (1.1 g, 0.0051 mol). Afterstirred at rt overnight, the mixture was concentrated to dry, thendiluted with aq. sodium bicarbonate, extracted with EtOAc. The combinedorganic layers were washed with brine, dried and concentrated to dry.The residue was applied on silica gel, eluting with 0 to 100% EtOAc inhexane, to yield the methyl amine compound (0.31 g, 85%). MS (ESI):(M+H)⁺=358.1.

Part 7.(3S,5S,6S)-5-(methoxycarbonyl)-1-methyl-6-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]piperidin-3-ylpiperidine-1-carboxylate

A solution ofmethyl(2S,3S,5S)-5-hydroxy-1-methyl-2-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]piperidine-3-carboxylate(72 mg, 0.00020 mol) in methylene chloride (2.0 mL, 0.031 mol) wastreated with N,N-carbonyldiimidazole (50 mg, 0.0003 mol) at rt for 2 h.To the mixture was added piperidine (0.060 mL, 0.00060 mol). Afterstirred at rt overnight, the mixture was concentrated to dry and useddirectly in next step.

Part 8.(3S,5S,6S)-5-[(hydroxyamino)carbonyl]-1-methyl-6-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]piperidin-3-ylpiperidine-1-carboxylate

To a solution of(3S,5S,6S)-5-(methoxycarbonyl)-1-methyl-6-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]piperidin-3-ylpiperidine-1-carboxylate(94 mg, 0.00020 mol) in methanol (0.8109 mL, 0.02002 mol) was added1.640 M of N-hydroxyamine in methanol (2.44 mL) made from thecorresponding salt and sodium methoxide. After stirred at rt for 1 h,the mixture was acidified with 1N HCl. The resultant mixture was applieddirectly on RP-HPLC to afford the product as a TFA salt (56 mg, 48%). MS(ESI): (M+H)⁺=471.1.

Example 177(3S,5S,6S)-5-[(hydroxyamino)carbonyl]-1-methyl-6-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]piperidin-3-yl(2S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 176. MS (ESI): (M+H)⁺=487.15.

Example 178(3S,5S,6S)-5-[(hydroxyamino)carbonyl]-1-methyl-6-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]piperidin-3-ylazepane-1-carboxylate

This compound was prepared using procedures analogous to those forexample 176. MS (ESI): (M+H)⁺=485.2.

Example 179(3S,5S,6S)-5-[(hydroxyamino)carbonyl]-1-methyl-6-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]piperidin-3-ylazetidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 176. MS (ESI): (M+H)⁺=443.2.

Example 180(3S,5S,6S)-5-[(hydroxyamino)carbonyl]-1-methyl-6-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]piperidin-3-yl dimethylcarbamate

This compound was prepared using procedures analogous to those forexample 176. MS (ESI): (M+H)⁺=431.1.

Example 181(3S,5S,6S)-5-[(hydroxyamino)carbonyl]-1-methyl-6-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]piperidin-3-yl2,5-dihydro-1H-pyrrole-1-carboxylate

This compound was prepared using procedures analogous to those forexample 176. MS (ESI): (M+H)⁺=455.1.

Example 182(3S,5S,6S)-5-[(hydroxyamino)carbonyl]-1-methyl-6-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]piperidin-3-ylpyrrolidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 176. MS (ESI): (M+H)⁺=457.1.

Example 183(3S,5S,6S)-5-[(hydroxyamino)carbonyl]-1-methyl-6-[(4-phenylpiperazin-1-yl)carbonyl]piperidin-3-ylazetidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 176. MS (ESI): (M+H)⁺=446.2.

Example 184(3S,5S,6S)-5-[(hydroxyamino)carbonyl]-1-methyl-6-[(3-phenyl-2,5-dihydro-1H-pyrrol-1-yl)carbonyl]piperidin-3-ylazetidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 176. MS (ESI): (M+H)⁺=429.2.

Example 185(3S,5S,6S)-6-(1,3-dihydro-2H-benzo[e]isoindol-2-ylcarbonyl)-5-[(hydroxyamino)carbonyl]-1-methylpiperidin-3-ylazetidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 176. MS (ESI): (M+H)⁺=453.2.

Example 186(3S,5S,6S)-5-[(hydroxyamino)carbonyl]-1-methyl-6-[(4-phenylpiperazin-1-yl)carbonyl]piperidin-3-ylpyrrolidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 176. MS (ESI): (M+H)⁺=460.2.

Example 187(3S,5S,6S)-5-[(hydroxyamino)carbonyl]-1-methyl-6-[(3R)-3-phenylpyrrolidin-1-yl]carbonylpiperidin-3-ylazetidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 176. MS (ESI): (M+H)⁺=431.2.

Example 188(3S,5S,6S)-5-[(hydroxyamino)carbonyl]-1-methyl-6-[(4-phenylpiperazin-1-yl)carbonyl]piperidin-3-ylpiperidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 176. MS (ESI): (M+H)⁺=474.2.

Example 189(3S,5S,6S)-6-(1,3-dihydro-2H-isoindol-2-ylcarbonyl)-5-[(hydroxyamino)carbonyl]-1-methylpiperidin-3-ylazetidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 176. MS (ESI): (M+H)⁺=403.2.

Example 190(3S,5S,6S)-5-[(hydroxyamino)carbonyl]-1-methyl-6-[(3-phenyl-2,5-dihydro-1H-pyrrol-1-yl)carbonyl]piperidin-3-ylpyrrolidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 176. MS (ESI): (M+H)⁺=443.05.

Example 191(3S,5S,6S)-5-[(hydroxyamino)carbonyl]-1-methyl-6-[(4-phenylpiperidin-1-yl)carbonyl]piperidin-3-ylpyrrolidine-1-carboxylate

A solution of(3S,5S,6S)-5-[(hydroxyamino)carbonyl]-1-methyl-6-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]piperidin-3-ylpyrrolidine-1-carboxylate (5.0 mg, 0.000011 mol) TFA salt in 1 mL ofMeOH was hydrogenated in the presence of 5% Pd/BaSO₄, under a balloonpressure of hydrogen, for 2 h. After filtered off the catalyst, thefiltration was concentrated to dry to give the product (5.0 mg, 100%).MS (ESI): (M+H)⁺=459.15.

Example 192(3S,5S,6S)-5-[(hydroxyamino)carbonyl]-1-methyl-6-[(4-phenylpiperidin-1-yl)carbonyl]piperidin-3-ylazepane-1-carboxylate

This compound was prepared using procedures analogous to those forexample 191. MS (ESI): (M+H)⁺=487.2.

Example 193(3S,5S,6S)-5-[(hydroxyamino)carbonyl]-1-methyl-6-[(4-phenylpiperidin-1-yl)carbonyl]piperidin-3-yl(2S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 191. MS (ESI): (M+H)⁺=489.2.

Example 194(3S,5S,6S)-5-[(hydroxyamino)carbonyl]-1-methyl-6-[(4-phenylpiperidin-1-yl)carbonyl]piperidin-3-ylpiperidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 191. MS (ESI): (M+H)⁺=473.2.

Example 195(3S,5S,6S)-5-[(hydroxyamino)carbonyl]-1-methyl-6-[(4-phenylpiperidin-1-yl)carbonyl]piperidin-3-yldimethylcarbamate

This compound was prepared using procedures analogous to those forexample 191. MS (ESI): (M+H)⁺=433.1.

Example 196methyl(2S,3S,5S)-3-[(hydroxyamino)carbonyl]-5-([(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]carbonyloxy)-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1-carboxylatePart 1dimethyl(2S,3S,5S)-5-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1,3-dicarboxylate

To a mixture of(2S,3S,5S)-5-hydroxy-3-(methoxycarbonyl)piperidine-2-carboxylic acid(1.10 g, 0.00541 mol), 1-phenyl-piperazine, (0.910 mL, 0.00595 mol) andbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(2.63 g, 0.00595 mol) in N,N-dimethylformamide (6.00 mL, 0.0775 mol) wasadded N,N-diisopropylethylamine (1.04 mL, 0.00595 mol) at 0 Celsius. Thereaction was stirred at rt for 3 h. To the reaction mixture was addedmethylene chloride (40.00 mL, 0.6240 mol), cat. amount of DMAP,N,N-diisopropylethylamine (2.36 mL, 0.0135 mol), followed by methylchloroformate (0.836 mL, 0.0108 mol) at 0 Celsius. The resultingreaction mixture was stirred at rt overnight. After quenched with water,the mixture was extracted with ethyl acetate. The combined organiclayers were washed with brine, dried and concentrated to dry. Theresidue was purified on silica gel, eluting with 0 to 100% EtOAc inhexane, to give The titled compound (1.88 g, 85.7%). MS (ESI):(M+H)⁺=406.2.

Part 2.dimethyl(2S,3S,5S)-5-([(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]carbonyloxy)-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1,3-dicarboxylate

To a solution ofdimethyl(2S,3S,5S)-5-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1,3-dicarboxylate(0.050 g, 0.00012 mol) in methylene chloride (1.00 mL, 0.0156 mol) wasadded N,N-carbonyldiimidazole (0.024 g, 0.0001480 mol). The reaction wasstirred at rt for 2 h. To the resultant mixture was added L-prolinol(0.01704 mL, 0.0001726 mol) and the reaction was stirred at rtovernight. The mixture was concentrated to dry in vacuo and useddirectly in next step. MS (ESI): (M+H)⁺=533.2.

Part 3.methyl(2S,3S,5S)-3-[(hydroxyamino)carbonyl]-5-([(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]carbonyloxy)-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1-carboxylate

To a solution ofdimethyl(2S,3S,5S)-5-([(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]carbonyloxy)-2-[4-phenylpiperazin-1-yl)carbonyl]piperidine-1,3-dicarboxylate(66 mg, 0.00012 mol) in methanol (0.57 mL, 0.014 mol) was added 1.640 Mof N-hydroxyamine in methanol solution (1.511 mL), made from thehydroxylamine HCl salt and sodium methoxide freshly. The mixture wasstirred at rt for 1 h and acidified with 1N HCl. The resulting mixturewas applied directly on RP-HPLC to yield the desired compound (61 mg,76%). MS (ESI): (M+H)⁺=534.2.

Example 197methyl(2S,3S,5S)-2-(1,3-dihydro-2H-isoindol-2-ylcarbonyl)-3-[(hydroxyamino)carbonyl]-5-[(pyrrolidin-1-ylcarbonyl)oxy]piperidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 196. MS (ESI): (M+H)⁺=461.2.

Example 198methyl(2S,3S,5S)-3-[(hydroxyamino)carbonyl]-2-[(4-phenylpiperazin-1-yl)carbonyl]-5-[(piperidin-1-ylcarbonyl)oxy]piperidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 196. MS (ESI): (M+H)⁺=518.15.

Example 199Methyl(2S,3S,5S)-3-[(hydroxyamino)carbonyl]-2-[(4-phenylpiperazin-1-yl)carbonyl]-5-[(pyrrolidin-1-ylcarbonyl)oxy]piperidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 196. MS (ESI): (M+H)⁺=504.2.

Example 200methyl(2S,3S,5S)-3-[(hydroxyamino)carbonyl]-2-[(3-phenylpyrrolidin-1-yl)carbonyl]-5-[(pyrrolidin-1-ylcarbonyl)oxy]piperidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 196. MS (ESI): (M+H)⁺=489.2.

Example 201methyl(2S,3S,5S)-5-[(dimethylamino)carbonyl]oxy-3-[(hydroxyamino)carbonyl]-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 196. MS (ESI): (M+H)⁺=478.1.

Example 202methyl(2S,3S,5S)-3-[(hydroxyamino)carbonyl]-2-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]-5-[(pyrrolidin-1-ylcarbonyl)oxy]piperidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 196. MS (ESI): (M+H)⁺=501.2.

Example 203methyl(2S,3S,5S)-3-[(hydroxyamino)carbonyl]-2-[(4-phenylpiperidin-1-yl)carbonyl]-5-[(pyrrolidin-1-ylcarbonyl)oxy]piperidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 191. MS (ESI): (M+H)⁺=503.2.

Example 204(3S,5S,6S)-5-[(hydroxyamino)carbonyl]-6-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]piperidin-3-ylpyrrolidine-1-carboxylate Part 1. 2-benzyl3-methyl(2S,3S,5S)-1-benzyl-5-[(pyrrolidin-1-ylcarbonyl)oxy]piperidine-2,3-dicarboxylate

To a solution of 2-benzyl3-methyl(2S,3S,5S)-1-benzyl-5-hydroxypiperidine-2,3-dicarboxylate (144mg, 0.000376 mol) in methylene chloride (2.0 mL, 0.031 mol) was addedN,N-carbonyldiimidazole (73.1 mg, 0.000451 mol). The reaction wasstirred at rt for 2 h. To the resulting mixture was added pyrrolidine(0.0470 mL, 0.000563 mol) and the reaction was stirred at rt overnight.The reaction was quenched with aq sodium bicarbonate, extracted withmethylene chloride. The combined organic layers were dried, purified onsilica gel (eluting with 0 to 40% EtOAc in hexane) to provide thecarbamate compound (160 mg, 88.7%). MS (ESI): (M+H)⁺=481.2.

Part 2.(2S,3S,5S)-3-(methoxycarbonyl)-5-[(pyrrolidin-1-ylcarbonyl)oxy]piperidine-2-carboxylicacid

A solution of 2-benzyl3-methyl(2S,3S,5S)-1-benzyl-5-[(pyrrolidin-1-ylcarbonyl)oxy]piperidine-2,3-dicarboxylate(144 mg, 0.000300 mol) in methanol (3.0 mL, 0.074 mol) was hydrogenatedin the presence of 10% Pd/C, under balloon pressure of hydrogen,overnight. After filtered off the catalyst, the filtration wasconcentrated to dry to provide crude product, which was used directly innext step.

Part 3.methyl(2S,3S,5S)-2-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]-5-[(pyrrolidin-1-ylcarbonyl)oxy]piperidine-3-carboxylate

To a mixture of(2S,3S,5S)-3-(methoxycarbonyl)-5-[(pyrrolidin-1-ylcarbonyl)oxy]piperidine-2-carboxylicacid (90.1 mg, 0.000300 mol) and 4-phenyl-1,2,3,6-tetrahydropyridine(64.6 mg, 0.000330 mol) HCl salt,benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(146 mg, 0.000330 mol) in N,N-dimethylformamide (0.44 mL, 0.0057 mol)was added N,N-diisopropylethylamine (0.115 mL, 0.000660 mol) at rt. Themixture was stirred at rt overnight, then quenched with aq. sodiumbicarbonate. After separation of the organic layers, the aq. layer wasextracted with EtOAc. The combined organic layers were washed withbrine, dried, and concentrated to dry. The crude material was useddirectly in next step.

Part 4.(3S,5S,6S)-5-[(hydroxyamino)carbonyl]-6-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]piperidin-3-ylpyrrolidine-1-carboxylate

A mixture of N-hydroxyamine hydrochloride (1.20 g, 0.0173 mol) in 4.5 mLof methanol was heated to at 55 Celsius. Sodium methoxide, 25 wt. %solution in methanol (5.925 mL, 0.06506 mol) was added. The resultingmixture was stirred at 55 Celsius for 5 min, then cooled to rt then at 0Celsius. Filtered off insolubles afforded a clear solution assumed to bec.a. 1.64 M of hydroxyamine in MeOH. The solution was prepared and usedfresh.

1.90 mL of the above prepared solution was added to a mixture of crudemethyl(2S,3S,5S)-2-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]-5-[(pyrrolidin-1-ylcarbonyl)oxy]piperidine-3-carboxylate(132.5 mg, 0.0003001 mol) in 1.43 mL of methanol. After stirred at rtfor 1 h, the mixture was adjusted to pH7 with 1N HCl (c.a. 1.9 mL). Theresulting mixture was applied directly on RP-HPLC to afford the targetedproduct (65 mg, 39%). MS (ESI): (M+H)⁺=443.2.

Example 205(3S,5S,6S)-6-(1,3-dihydro-2H-benzo[e]isoindol-2-ylcarbonyl)-5-[(hydroxyamino)carbonyl]piperidin-3-ylazetidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 204. MS (ESI): (M+H)⁺=439.2.

Example 206(3S,5S,6S)-6-(1,3-dihydro-2H-isoindol-2-ylcarbonyl)-5-[(hydroxyamino)carbonyl]piperidin-3-ylazetidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 204. MS (ESI): (M+H)⁺=389.2.

Example 207(3S,5S,6S)-5-[(hydroxyamino)carbonyl]-6-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]piperidin-3-ylazetidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 204. MS (ESI): (M+H)⁺=429.2.

Example 208(3S,5S,6S)-5-[(hydroxyamino)carbonyl]-6-[(3R)-3-phenylpyrrolidin-1-yl]carbonylpiperidin-3-ylazetidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 204. MS (ESI): (M+H)⁺=417.2.

Example 209(3S,5S,6S)-5-[(hydroxyamino)carbonyl]-6-[(4-phenylpiperazin-1-yl)carbonyl]piperidin-3-ylazetidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 204. MS (ESI): (M+H)⁺=432.2.

Example 210(3S,5S,6S)-5-[(hydroxyamino)carbonyl]-6-[(3-phenyl-2,5-dihydro-1H-pyrrol-1-yl)carbonyl]piperidin-3-ylazetidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 204. MS (ESI): (M+H)⁺=415.2.

Example 211(3S,5S,6S)-5-[(hydroxyamino)carbonyl]-6-[(4-phenylpiperidin-1-yl)carbonyl]piperidin-3-ylazetidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 191. MS (ESI): (M+H)⁺=431.3.

Example 212(3S,5S,6S)-5-[(hydroxyamino)carbonyl]-6-[(4-phenylpiperidin-1-yl)carbonyl]piperidin-3-ylpyrrolidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 191. MS (ESI): (M+H)⁺=445.2.

Example 213methyl(2S,3S,5S)-3-[(hydroxyamino)carbonyl]-5-(2-oxo-2-pyrrolidin-1-ylethoxy)-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1-carboxylatePart 1.dimethyl(2S,3S,5S)-5-(2-tert-butoxy-2-oxoethoxy)-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1,3-dicarboxylate

To a solution ofdimethyl(2S,3S,5S)-5-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1,3-dicarboxylate(50.0 mg, 0.000123 mol) in tetrahydrofuran (0.50 mL, 0.0062 mol) wasadded 1.00 M of potassium tert-butoxide in tetrahydrofuran (0.150 mL).After stirred at rt for 30 min, to the mixture was added bromo-aceticacid 1,1-dimethylethyl ester (0.0228 mL, 0.000154 mol). The resultingmixture was stirred at rt overnight and then concentrated to dry.

Part 2.((3S,5S,6S)-1,5-bis(methoxycarbonyl)-6-[(4-phenylpiperazin-1-yl)carbonyl]piperidin-3-yloxy)aceticacid

The crude mixture made above was treated with 1 mL of TFA at rt for 30min. After concentrated to dry, the crude residue was used directly innext step.

Part 3.dimethyl(2S,3S,5S)-5-(2-oxo-2-pyrrolidin-1-ylethoxy)-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1,3-dicarboxylate

To a mixture of((3S,5S,6S)-1,5-bis(methoxycarbonyl)-6-[(4-phenylpiperazin-1-yl)carbonyl]piperidin-3-yloxy)aceticacid (57 mg, 0.00012 mol), pyrrolidine (0.0308 mL, 0.000369 mol), andbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(163 mg, 0.000369 mol) in N,N-dimethylformamide (0.50 mL, 0.0064 mol)was added N,N-diisopropylethylamine (0.0857 mL, 0.000492 mol). Themixture was stirred at rt for 2 h, then diluted with ethyl acetate,washed with water, brine and dried. After concentrated to dry, theresidue was used directly in next step.

Part 4.methyl(2S,3S,5S)-3-[(hydroxyamino)carbonyl]-5-(2-oxo-2-pyrrolidin-1-ylethoxy)-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1-carboxylate

To the reaction mixture ofdimethyl(2S,3S,5S)-5-(2-oxo-2-pyrrolidin-1-ylethoxy)-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1,3-dicarboxylate(64 mg, 0.00012 mol) in methanol (0.5018 mL, 0.01239 mol) was added1.640 M of N-hydroxyamine in methanol solution (1.51 mL) made from thecorresponding salt and sodium methoxide. After stirred at rt for 1 h,the mixture was acidified with 1N HCl. The resultant mixture was applieddirectly on RP-HPLC to afford the product as a TFA salt (14 mg, 18%). MS(ESI): (M+H)⁺=518.2.

Example 214methyl(2S,3S,5S)-3-[(hydroxyamino)carbonyl]-2-[(4-phenylpiperazin-1-yl)carbonyl]-5-(phenylthio)piperidine-1-carboxylatePart 1.dimethyl(2S,3S,5R)-5-[(methylsulfonyl)oxy]-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1,3-dicarboxylate

To a stirred solution ofdimethyl(2S,3S,5R)-5-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1,3-dicarboxylate(1.00 g, 0.00247 mol) and triethylamine (0.412 mL, 0.00296 mol) inmethylene chloride (20.00 mL, 0.3120 mol) was added methanesulfonylchloride (0.210 mL, 0.00271 mol). The mixture was stirred at rtovernight. After quenched with MeOH, the mixture was evaporated to dryin vacuo and diluted with ethyl acetate. The organic layers were washedwith water, brine and dried, concentrated to dry. The residue waspurified on silica gel, eluting with 0 to 80% EtOAc in hexane, togenerate the mesylate compound (0.98 g, 82%). MS (ESI): (M+H)⁺=484.1.

Part 2.dimethyl(2S,3S,5S)-2-[(4-phenylpiperazin-1-yl)carbonyl]-5-(phenylthio)piperidine-1,3-dicarboxylate

To a mixture ofdimethyl(2S,3S,5R)-5-[(methylsulfonyl)oxy]-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1,3-dicarboxylate(50.0 mg, 0.000103 mol) and benzenethiol (0.0149 mL, 0.000145 mol) intetrahydrofuran (0.50 mL, 0.0062 mol) was added 1.00 M of potassiumtert-butoxide in tetrahydrofuran (0.150 mL). The mixture was stirred atrt overnight. The reaction mixture was carried directly into next step.

Part 3.methyl(2S,3S,5S)-3-[(hydroxyamino)carbonyl]-2-[(4-phenylpiperazin-1-yl)carbonyl]-5-(phenylthio)piperidine-1-carboxylate

To the reaction mixture ofdimethyl(2S,3S,5S)-2-[(4-phenylpiperazin-1-yl)carbonyl]-5-(phenylthio)piperidine-1,3-dicarboxylate(51 mg, 0.00010 mol) in tetrahydrofuran (0.50 mL, 0.0062 mol) was added1.640 M of N-hydroxyamine in methanol (1.25 mL) made from thecorresponding salt and sodium methoxide. After stirred at rt for 1 h,the mixture was acidified with 1N HCl. The resultant mixture was applieddirectly on RP-HPLC to afford the product as a TFA salt (39 mg, 63%). MS(ESI): (M+H)⁺=499.1.

Example 215methyl(2S,3S,5S)-5-(allyloxy)-3-[(hydroxyamino)carbonyl]-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1-carboxylatePart 1.dimethyl(2S,3S,5S)-5-[(allyloxy)carbonyl]oxy-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1,3-dicarboxylate

To a solution ofdimethyl(2S,3S,5S)-5-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1,3-dicarboxylate(0.1000 g, 0.0002466 mol) in methylene chloride (1.00 mL, 0.0156 mol)was added triethylamine (0.04469 mL, 0.0003206 mol), catalytic amount ofDAMP, followed by allyl chloroformate (0.03146 mL, 0.0002960 mol). Themixture was stirred at rt overnight, then quenched with aq. sodiumbicarbonate and extracted with methylene chloride. The combined organiclayers were dried and concentrated to dry. The residue was purified oncolumn, eluting with 0 to 100% EtOAc in hexane, to yield thecorresponding carbonate (0.11 g, 91%). MS (ESI): (M+H)⁺=490.2.

Part 2.dimethyl(2S,3S,5S)-5-(allyloxy)-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1,3-dicarboxylate

A mixture ofdimethyl(2S,3S,5S)-5-[(allyloxy)carbonyl]oxy-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1,3-dicarboxylate(100 mg, 0.0002 mol) and tetrakis(triphenylphosphine)palladium(O) (24mg, 0.000020 mol) in tetrahydrofuran (5.00 mL, 0.0616 mol) was refluxedfor 2 h. The mixture was concentrated to dry and used directly in nextstep.

Part 3.methyl(2S,3S,5S)-5-(allyloxy)-3-[(hydroxyamino)carbonyl]-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1-carboxylate

To a solution ofdimethyl(2S,3S,5S)-5-(allyloxy)-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1,3-dicarboxylate(80 mg, 0.0002 mol) in methanol (0.79 mL, 0.020 mol) was added 1.640 Mof N-hydroxyamine in Methanol (2 mL), made by treatment of thecorresponding hydroxylamine HCl salt with sodium methoxide. The mixturewas stirred at rt for 1 h, then acidified with 1N HCl and applied onRP-HPLC directly to give The titled compound as a TFA salt (23 mg, 23%).MS (ESI): (M+H)⁺=447.1.

Example 216methyl(2S,3S,5S)-3-[(hydroxyamino)carbonyl]-2-[(4-phenylpiperazin-1-yl)carbonyl]-5-propoxypiperidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 191. MS (ESI): (M+H)⁺=449.2.

Example 217methyl(2S,3S,5S)-3-[(hydroxyamino)carbonyl]-5-methoxy-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1-carboxylatePart 1. 2-benzyl3-methyl(2S,3S,5S)-1-benzyl-5-methoxypiperidine-2,3-dicarboxylate

Diazomethane was generated (from 5 g of Diazald) and distilled togetherwith ether into a mixture of 2-benzyl3-methyl(2S,3S,5S)-1-benzyl-5-hydroxypiperidine-2,3-dicarboxylate (0.60g, 0.0016 mol) and around 1 g of silica gel in 10 mL of ether. Afterdistillation, the mixture was stirred at rt overnight. The mixture wasdiluted with methylene chloride, filtered to remove silica gel. Thefiltration was concentrated to dry and the resulting residue was appliedon column, eluting with 0 to 40% EtOAc in Hexane, to yield the methylether compound (20 mg, 3.2%). MS (ESI): (M+H)⁺=398.1.

Part 2. (2S,3S,5S)-5-methoxy-3-(methoxycarbonyl)piperidine-2-carboxylicacid

A solution of 2-benzyl3-methyl(2S,3S,5S)-1-benzyl-5-methoxypiperidine-2,3-dicarboxylate (30.0mg, 0.0000755 mol) in 2 mL of MeOH was hydrogenated in the presence of10% Pd/C, under a balloon pressure of hydrogen, for 1 h. The catalystwas filtered off and the filtration was concentrated to dry. The residuewas used directly in next step (16 mg, 97.6%). MS (ESI): (M+H)⁺=218.0.

Part 3.methyl(2S,3S,5S)-5-methoxy-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-3-carboxylate

To a mixture of(2S,3S,5S)-5-methoxy-3-(methoxycarbonyl)piperidine-2-carboxylic acid(14.0 mg, 0.0000644 mol), 1-phenyl-piperazine (0.01231 mL, 8.056E-5 mol)and benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate (35.63 mg, 8.056E-5 mol) in N,N-dimethylformamide(0.20 mL, 0.0026 mol) was added N,N-diisopropylethylamine (0.01403 mL,8.056E-5 mol). The mixture was stirred at rt for 2 h. After quenchedwith water, the mixture was extracted with ethyl acetate. The combineorganic lyers were washed with brine, dried and concentrated to dry. Theresidue was used directly in next step without further purification. MS(ESI): (M+H)⁺=362.1.

Part 4.dimethyl(2S,3S,5S)-5-methoxy-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1,3-dicarboxylate

To a mixture ofmethyl(2S,3S,5S)-5-methoxy-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-3-carboxylate(0.0233 g, 0.0000645 mol) and 4-dimethylaminopyridine (0.0118 g,0.0000967 mol) in methylene chloride (1.00 mL, 0.0156 mol) was addedmethyl chloroformate (0.00648 mL, 0.0000838 mol). The reaction wasstirred at rt overnight. After quenched with aq. sodium bicaronate, thereaction was extracted with ethyl acetate. The combined organic layerswere washed with brine, dried, concentrated to dry. The resultingresidue was used directly in next step. MS (ESI): (M+H)⁺=420.2.

Part 5.methyl(2S,3S,5S)-3-[(hydroxyamino)carbonyl]-5-methoxy-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1-carboxylate

To a solution ofdimethyl(2S,3S,5S)-5-methoxy-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1,3-dicarboxylate(0.027 g, 0.000064 mol) in methanol (0.30 mL, 0.0074 mol) was added1.640 M of N-hydroxyamine in methanol (0.7850 mL), freshly made from thecorresponding hydroxylamine HCl salt and sodium methoxide. The mixturewas stirred at rt for 1 h, then acidified with 1N HCl. The crude mixturewas applied directly on RP-HPLC to afford the product as a TFA salt (23mg, 68%). MS (ESI): (M+H)⁺=421.2.

Example 218(2S,3S,5S)-5-tert-butoxy-N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-3-carboxamidePart 1. 2-benzyl3-methyl(2S,3S,5S)-1-benzyl-5-tert-butoxypiperidine-2,3-dicarboxylate

Isobutylene (2.96 mL, 0.0313 mol) was collected at −78 Celsius. To thecold isobutylene was added 2-benzyl3-methyl(2S,3S,5S)-1-benzyl-5-hydroxypiperidine-2,3-dicarboxylate (0.60g, 0.0016 mol) tetrahydrofuran (3.00 mL, 0.0370 mol), sulfuric acid(0.021 mL, 0.00039 mol). The reaction was sealed and allowed to warm upto rt and stirred at rt overnight. The mixture was cooled to −78 Celsiusagain. The seal was replaced with a septa connecting with a balloon. Thereaction was then allowed to warm up to rt gradually to allow theevaporating of excess isobutylene. The residue was diluted with EtOAc,neutralized with aq. sodium hydroxide. The organic layers were washedwith brine, dried. The residue was purified on silica gel, eluting with0 to 30% EtOAc in hexane, to afford the tert-butyl ether (0.35 g, 51%).MS (ESI): (M+H)⁺=440.25.

Part 2.(2S,3S,5S)-5-tert-butoxy-3-(methoxycarbonyl)piperidine-2-carboxylic acid

A solution of 2-benzyl3-methyl(2S,3S,5S)-1-benzyl-5-tert-butoxypiperidine-2,3-dicarboxylate(80.0 mg, 0.000182 mol) in 5 mL of MeOH was hydrogenated in the presenceof 10% Pd/C, under a balloon pressure of hydrogen, overnight. Afterfilter off the catalyst, the filtration was concentrated to dry and useddirectly in next step (43 mg, 91.1%). MS (ESI): (M+H)⁺=260.1.

Part 3.methyl(2S,3S,5S)-5-tert-butoxy-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-3-carboxylate

To a mixture of(2S,3S,5S)-5-tert-butoxy-3-(methoxycarbonyl)piperidine-2-carboxylic acid(43.0 mg, 0.000166 mol), 1-phenyl-piperazine (0.03166 mL, 0.0002073 mol)and benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate (0.09168 g, 0.0002073 mol) in N,N-dimethylformamide(0.40 mL, 0.0052 mol) was added N,N-diisopropylethylamine (0.03611 mL,0.0002073 mol). The reaction was stirred at rt for 2 h, then quenchedwith water. The mixture was extracted with ethyl acetate. The combinedorganic layers were washed with brine, dried and concentrated to dry.The residue was used directly in next step. MS (ESI): (M+H)⁺=404.2.

Part 4.(2S,3S,5S)-5-tert-butoxy-N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-3-carboxamide(3a)

To a solution ofmethyl(2S,3S,5S)-5-tert-butoxy-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-3-carboxylate(0.03345 g, 8.290E-5 mol) in Methanol (0.30 mL, 0.0074 mol) was added1.640 M of N-hydroxyamine in Methanol (1.011 mL), freshly made from thecorresponding HCl salt and sodium methoxide. The mixture was stirred atrt for 1 h then acidified with 1N HCl. The resulting mixture was applieddirectly on RP-HPLC to provide the product as TFA salt (21 mg, 49%). MS(ESI): (M+H)⁺=405.1.

Example 219methyl(2S,3S,5S)-5-tert-butoxy-3-[(hydroxyamino)carbonyl]-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1-carboxylatePart 1.dimethyl(2S,3S,5S)-5-tert-butoxy-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1,3-dicarboxylate

To a mixture ofmethyl(2S,3S,5S)-5-tert-butoxy-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-3-carboxylate(0.03345 g, 8.290E-5 mol) and 4-dimethylaminopyridine (0.0152 g,0.000124 mol) in methylene chloride (1.50 mL, 0.0234 mol) was addedmethyl chloroformate (0.00833 mL, 0.000108 mol). The reaction wasstirred at rt overnight. After quenched with aq. sodium bicaronate, thereaction was extracted with ethyl acetate. The combined organic layerswere washed with brine, dried, concentrated to dry. The resultingresidue was used directly in next step. MS (ESI): (M+H)⁺=462.2.

Part 2.methyl(2S,3S,5S)-5-tert-butoxy-3-[(hydroxyamino)carbonyl]-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1-carboxylate

To a solution ofdimethyl(2S,3S,5S)-5-tert-butoxy-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1,3-dicarboxylate(0.038 g, 0.000082 mol) in methanol (0.30 mL, 0.0074 mol) was added1.640 M of N-hydroxyamine in methanol (1.004 mL), freshly made from thecorresponding hydroxylamine HCl salt and sodium methoxide. The mixturewas stirred at rt for 1 h then acidified with 1N HCl. The resultingmixture was applied directly on RP-HPLC to give the targeted product asa TFA salt (10 mg, 45%). MS (ESI): (M+H)⁺=463.2.

Example 220(3R,4S)-1-[(E)-(cyanoimino)(pyrrolidin-1-yl)methyl]-N-hydroxy-4-[(3R)-3-phenylpyrrolidin-1-yl]carbonylpiperidine-3-carboxamidePart 1.methyl(3R,4S)-1-[(Z)-(cyanoimino)(phenoxy)methyl]-4-[(3R)-3-phenylpyrrolidin-1-yl]carbonylpiperidine-3-carboxylate

To a stirred solution of(3R,4S)-4-((R)-3-Phenyl-pyrrolidine-1-carbonyl)-piperidine-3-carboxylicacid methyl ester (654 mg, 0.00207 mol) in anhydrous acetonitrile (11.0mL, 0.211 mol) at rt was added triethylamine (0.579 mL, 0.00413 mol) anddiphenyl cyanocarbonimidate (762 mg, 0.00310 mol). The reaction mixturewas heated to reflux (oil bath temperature: 85° C.) for 18 h. Thereaction mixture was concentrated in vacuo. The residue was purified byCombiflash with 40-90% EtOAc/Hex to give the product as a colorlesssolid (841 mg, 88% in yield). MS (ESI): (M+H)⁺=461.1.

Part 2.(3R,4S)-1-[(E)-Cyanoimino]-pyrrolidin-1-yl-methyl-4-((R)-3-phenyl-pyrrolidine-1-carbonyl)-piperidine-3-carboxylicacid methyl ester

To a stirred solution ofmethyl(3R,4S)-1-[(Z)-(cyanoimino)(phenoxy)methyl]-4-[(3R)-3-phenylpyrrolidin-1-yl]carbonylpiperidine-3-carboxylate(112 mg, 0.000243 mol) in anhydrous isopropyl alcohol (3.00 mL, 0.0392mol) was added pyrrolidine (61.5 uL, 0.000730 mol). The reaction mixturewas heated to reflux (oil bath temperature: 85° C.) for 18 h. Thereaction mixture was concentrated in vacuo. The residue was purified byCombiflash with 0-5% MeOH/CH₂Cl₂ to give the product as a colorlesssolid (90 mg, 85% in yield). MS (ESI): (M+H)⁺=438.2.

Part 3.(3R,4S)-1-[(E)-(cyanoimino)(pyrrolidin-1-yl)methyl]-N-hydroxy-4-[(3R)-3-phenylpyrrolidin-1-yl]carbonylpiperidine-3-carboxamide

Preparation of 1.50 M NH₂OH/NaOMe in MeOH: To a stirred suspension ofhydroxylamine hydrochloride (2.106 g, 0.03000 mol) in anhydrous methanol(9.0 mL) at rt was added 4.37 M of sodium methoxide in methanol (10.3mL). The reaction mixture was heated at 55° C. for 5 min, cooled to rt,then to 0° C. Filtration afforded a clear solution assumed to be ca.1.50 M in methanol.

To a stirred solution of (3R,4S)-1-[(E)-cyanoimino]-pyrrolidin-1-yl-methyl-4-((R)-3-phenyl-pyrrolidine-1-carbonyl)-piperidine-3-carboxylicacid methyl ester (90.0 mg, 0.000206 mol) in anhydrous methanol (1.5 mL,0.037 mol) at rt was added the above 1.50 M of

Hydroxylamine in methanol (2.74 mL). The reaction mixture was stirred atrt for 1 h 15 min. LCMS showed the reaction was done. The reaction wasquenched with saturated aqueous NH₄Cl (20 mL), extracted with EtOAc(2×). The combined organic layers were washed with brine, dried oversodium sulfate, filtered and concentrated in vacuo. The residue waspurified by reverse phase HPLC with 5-95% MeCN/H₂O (0.05% NH₄OH) to givethe pure product as a colorless solid (57.2 mg, 63% in yield). MS (ESI):(M+H)⁺=439.2.

Example 221(3R,4S)-1-[(E)-azetidin-1-yl(cyanoimino)methyl]-N-hydroxy-4-[(3R)-3-phenylpyrrolidin-1-yl]carbonylpiperidine-3-carboxamide

The titled compound was prepared using procedures analogous to those inExample 220. MS (ESI): (M+H)⁺=425.2.

Example 222(3R,4S)-1-[(E)-(cyanoimino)(dimethylamino)methyl]-N-hydroxy-4-[(3R)-3-phenylpyrrolidin-1-yl]carbonylpiperidine-3-carboxamide

The titled compound was prepared using procedures analogous to those inExample 220. MS (ESI): (M+H)⁺=413.2.

Example 223(3R,4S)-1-[(E)-(cyanoimino)(cyclopropylamino)methyl]-N-hydroxy-4-[(3R)-3-phenylpyrrolidin-1-yl]carbonylpiperidine-3-carboxamide

The titled compound was prepared using procedures analogous to those inExample 220. MS (ESI): (M+H)⁺=425.2.

Example 224(3R,4S)-1-[(E)-(cyanoimino)(piperidin-1-yl)methyl]-N-hydroxy-4-[(3R)-3-phenylpyrrolidin-1-yl]carbonylpiperidine-3-carboxamide

The titled compound was prepared using procedures analogous to those inExample 220. MS (ESI): (M+H)⁺=453.3.

Example 225(3R,4S)-1-[(Z)-(cyanoimino)(morpholin-4-yl)methyl]-N-hydroxy-4-[(3R)-3-phenylpyrrolidin-1-yl]carbonylpiperidine-3-carboxamide

The titled compound was prepared using procedures analogous to those inExample 220. MS (ESI): (M+H)⁺=455.3.

Example 226(3R,4S)-1-[(Z)-(cyanoimino)(hydroxyamino)methyl]-N-hydroxy-4-[(3R)-3-phenylpyrrolidin-1-yl]carbonylpiperidine-3-carboxamide

The titled compound was prepared using procedures analogous to those inExample 220. MS (ESI): (M+H)⁺=401.2.

Example 227(3R,4S)-1-[(E)-azepan-1-yl(cyanoimino)methyl]-N-hydroxy-4-[(3R)-3-phenylpyrrolidin-1-yl]carbonylpiperidine-3-carboxamide

The titled compound was prepared using procedures analogous to those inExample 220. MS (ESI): (M+H)⁺=467.3.

Example 228(3R,4S)-1-[(Z)-(cyanoimino)(4-methylpiperazin-1-yl)methyl]-N-hydroxy-4-[(3R)-3-phenylpyrrolidin-1-yl]carbonylpiperidine-3-carboxamide

The titled compound was prepared using procedures analogous to those inExample 220. MS (ESI): (M+H)⁺=468.2.

Example 229(3R,4S)-1-[(Z)-(cyanoimino)(thiomorpholin-4-yl)methyl]-N-hydroxy-4-[(3R)-3-phenylpyrrolidin-1-yl]carbonylpiperidine-3-carboxamide

The titled compound was prepared using procedures analogous to those inExample 220. MS (ESI): (M+H)⁺=471.1.

Example 230(3R,4S)-1-[(E)-(cyanoimino)(4-methylpiperidin-1-yl)methyl]-N-hydroxy-4-[(3R)-3-phenylpyrrolidin-1-yl]carbonylpiperidine-3-carboxamide

The titled compound was prepared using procedures analogous to those inExample 220. MS (ESI): (M+H)⁺=467.2.

Example 231(3R,4S)-1-[(Z)-(cyanoimino)(2,5-dihydro-1H-pyrrol-1-yl)methyl]-N-hydroxy-4-[(3R)-3-phenylpyrrolidin-1-yl]carbonylpiperidine-3-carboxamide

The titled compound was prepared using procedures analogous to those inExample 220. MS (ESI): (M+H)⁺=437.2.

Example 232(3R,4S)-1-[(Z)-(cyanoimino)(1,3-dihydro-2H-isoindol-2-yl)methyl]-N-hydroxy-4-[(3R)-3-phenylpyrrolidin-1-yl]carbonylpiperidine-3-carboxamide

The titled compound was prepared using procedures analogous to those inExample 220. MS (ESI): (M+H)⁺=487.1.

Example 233(3R,4S)-1-[(Z)-(cyanoimino)(3,4-dihydroisoquinolin-2(1H)-yl)methyl]-N-hydroxy-4-[(3R)-3-phenylpyrrolidin-1-yl]carbonylpiperidine-3-carboxamide

The titled compound was prepared using procedures analogous to those inExample 220. MS (ESI): (M+H)⁺=501.1.

Example 234(3R,4S)—N-hydroxy-1-[(Z)-1-(hydroxyamino)-2-nitrovinyl]-4-[(3R)-3-phenylpyrrolidin-1-yl]carbonylpiperidine-3-carboxamidePart 1.methyl(3R,4S)-1-[(Z)-1-(methylthio)-2-nitrovinyl]-4-[(3R)-3-phenylpyrrolidin-1-yl]carbonylpiperidine-3-carboxylate

To a stirred solution of(3R,4S)-4-((R)-3-phenyl-pyrrolidine-1-carbonyl)-piperidine-3-carboxylicacid methyl ester (3.10E2 mg, 0.000980 mol) in anhydrous acetonitrile(9.8 mL, 0.19 mol) at rt was added triethylamine (274 uL, 0.00196 mol)and 1,1-bis(methylthio)-2-nitroethylene (248 mg, 0.00147 mol). Thereaction mixture was heated to reflux (oil bath temperature: 85° C.) for19 h. The reaction mixture was concentrated in vacuo. The residue waspurified by Combiflash with 40-95% EtOAc/Hex to give the product as ayellow viscous oil (227 mg, 53% in yield). MS (ESI): (M+H)⁺=434.1.

Part 2.methyl(3R,4S)-1-[(E)-2-nitro-1-piperidin-1-ylvinyl]-4-[(3R)-3-phenylpyrrolidin-1-yl]carbonylpiperidine-3-carboxylate

To a stirred solution ofmethyl(3R,4S)-1-[(Z)-1-(methylthio)-2-nitrovinyl]-4-[(3R)-3-phenylpyrrolidin-1-yl]carbonylpiperidine-3-carboxylate(81.0 mg, 0.000187 mol) in ethanol (3.0 mL, 0.051 mol) was addedpiperidine (92.8 uL, 0.000934 mol). The reaction mixture was heated toreflux (oil bath temperature: 85° C.) for 17 h 45 min. The reactionmixture was concentrated in vacuo. The residue was purified byCombiflash with 0-8% MeOH/CH₂Cl₂ to give the product as a yellow solid(62 mg, 71% in yield). MS (ESI): (M+H)⁺=471.1.

Part 3.(3R,4S)—N-hydroxy-1-[(Z)-1-(hydroxyamino)-2-nitrovinyl]-4-[(3R)-3-phenylpyrrolidin-1-yl]carbonylpiperidine-3-carboxamide

To a stirred solution ofmethyl(3R,4S)-1-[(E)-2-nitro-1-piperidin-1-ylvinyl]-4-[(3R)-3-phenylpyrrolidin-1-yl]carbonylpiperidine-3-carboxylate(62.0 mg, 0.000132 mol) in anhydrous methanol (1.0 mL, 0.025 mol) wasadded 1.50 M of hydroxylamine in Methanol (1.76 mL). The reactionmixture was stirred at rt for 2 h. The reaction was quenched withsaturated aqueous NH₄Cl (20 mL), extracted with EtOAc (2×). The combinedorganic layers were washed with brine, dried over sodium sulfate,filtered and concentrated in vacuo. The residue was purified by reversephase HPLC with 5-95% MeCN/H₂O to give the pure product as a colorlesssolid (14.3 mg, 26% in yield). MS (ESI): (M+Na)⁺=442.2.

Example 235(3R,4S)-1-[(E)-(cyanoimino)(piperidin-1-yl)methyl]-4-[4-(4-cyano-2-methylphenyl)piperazin-1-yl]carbonyl-N-hydroxypiperidine-3-carboxamidePart 1. 1-benzyl3-methyl(3R,4S)-4-[4-(4-cyano-2-methylphenyl)piperazin-1-yl]carbonylpiperidine-1,3-dicarboxylate

To a stirred mixture of (3R,4S)-piperidine-1,3,4-tricarboxylic acid1-benzyl ester 3-methyl ester (0.554 g, 0.00172 mol) inN,N-dimethylformamide (8.500 mL, 0.1098 mol) was added3-methyl-4-piperazin-1-ylbenzonitrile dihydrochloride (0.6146 g,0.002241 mol), (benzotriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphate (1.017 g, 0.001896 mol), and,N,N-diisopropylethylamine (1.509 mL, 0.008620 mol). The reaction mixturewas stirred overnight at room temp. Reaction quenched with KH₂PO₄ (satsolution). Layers separated and aq layer extracted with ethyl acetate3×. Organic layers were washed with brine and dried over magnesiumsulfate. Filtered and concentrated. The residue was purified byCombiflash with 40-70% EtOAc/Hex to give the product (75% in yield). MS(ESI): (M+H)⁺=505.

Part 2.methyl(3R,4S)-4-[4-(4-cyano-2-methylphenyl)piperazin-1-yl]carbonylpiperidine-3-carboxylate

To a solution of 1-benzyl3-methyl(3R,4S)-4-[4-(4-cyano-2-methylphenyl)piperazin-1-yl]carbonylpiperidine-1,3-dicarboxylate(0.5265 g, 0.001043 mol) in methanol (11.00 mL, 0.2716 mol) was added10% palladium (93.9 mg, 0.0000883 mol) on carbon at room temp. Thereaction mixture was stirred under hydrogen balloon at 1 atm pressureovernight. After overnight stirring reaction mixture was filtered andconcentrated to give the product in quantitative yield. MS (ESI):(M+H)⁺=371.

Part 3.methyl(3R,4S)-1-[(Z)-(cyanoimino)(phenoxy)methyl]-4-[4-(4-cyano-2-methylphenyl)piperazin-1-yl]carbonylpiperidine-3-carboxylate

To a stirred solution ofmethyl(3R,4S)-4-[4-(4-cyano-2-methylphenyl)piperazin-1-yl]carbonylpiperidine-3-carboxylate(386.500 mg, 1.04334E-3 mol) in anhydrous acetonitrile (6.000 mL, 0.1149mol) at rt was added triethylamine (0.2923 mL, 0.002087 mol) anddiphenyl cyanocarbonimidate (384.4 mg, 0.001565 mol). The reactionmixture was heated to reflux (oil bath temperature: 85° C.) for 5 hrs.The reaction mixture was concentrated in vacuo. The residue was purifiedby Combiflash with 40-90% EtOAc/Hex to give the product (60% in yield).MS (ESI): (M+H)⁺=515.

Part 4.methyl(3R,4S)-1-[(E)-(cyanoimino)(piperidin-1-yl)methyl]-4-[4-(4-cyano-2-methylphenyl)piperazin-1-yl]carbonylpiperidine-3-carboxylate

To a stirred solution ofmethyl(3R,4S)-1-[(Z)-(cyanoimino)(phenoxy)methyl]-4-[4-(4-cyano-2-methylphenyl)piperazin-1-yl]carbonylpiperidine-3-carboxylate(52 mg, 0.00010 mol) in acetonitrile (2.006 mL, 0.03840 mol) was addedpiperidine (0.200 mL, 0.00202 mol). The reaction mixture refluxed (oilbath at 85 deg). Upon completion reaction mixture concentrated invacuum. The residue was purified by combiflash using 0-5%methanol/dichloromethane to give the product (53.3 mg, 98% in yield). MS(ESI): (M+H)⁺=506.

Part 5.(3R,4S)-1-[(E)-(cyanoimino)(piperidin-1-yl)methyl]-4-[4-(4-cyano-2-methylphenyl)piperazin-1-yl]carbonyl-N-hydroxypiperidine-3-carboxamide

Preparation of 1.50 M NH₂OH/NaOMe in MeOH: To a stirred suspension ofhydroxylamine hydrochloride (1.56573 g, 0.0223062 mol) in anhydrousmethanol (6.0 mL) at rt was added 4.37 M of sodium methoxide in methanol(7.64 mL). The reaction mixture was heated at 55° C. for 5 min, cooledto rt, then to 0° C. Filtration afforded a clear solution assumed to beca. 1.50 M in methanol. To a stirred solution ofmethyl(3R,4S)-1-[(E)-(cyanoimino)(piperidin-1-yl)methyl]-4-[4-(4-cyano-2-methylphenyl)piperazin-1-yl]carbonylpiperidine-3-carboxylate(53.30 mg, 0.0001054 mol) in anhydrous methanol (1.110 mL, 0.02740 mol)at rt was added the above 1.50 M of hydroxylamine in methanol (1.40 mL).The reaction mixture was stirred at rt for 2 h. LCMS showed the reactionwas done. The reaction was quenched with saturated aqueous NH₄Cl,extracted with EtOAc (2×). The combined organic layers were washed withbrine, dried over sodium sulfate, filtered and concentrated in vacuo.The residue was purified by reverse phase HPLC with 5-95% MeCN/H₂O togive the product. MS (ESI): (M+H)⁺=507.

Example 236(3R,4S)-1-[(E)-(cyanoimino)(dimethylamino)methyl]-4-[4-(4-cyano-2-methylphenyl)piperazin-1-yl]carbonyl-N-hydroxypiperidine-3-carboxamide

The titled compound was prepared using procedures analogous to those inExample 235. MS (ESI): (M+H)⁺=467.

Example 237(3R,4S)-1-[(E)-azepan-1-yl)cyanoimino)methyl]-4-[4-(4-cyano-2-methylphenyl)piperazin-1-yl]carbonyl-N-hydroxypiperidine-3-carboxamide

The titled compound was prepared using procedures analogous to those inExample 235. MS (ESI): (M+H)⁺=521.

Example 238(3R,4S)-1-[(E)-(cyanoimino)(pyrrolidin-1-yl)methyl]-4-[4-(4-cyano-2-methylphenyl)piperazin-1-yl]carbonyl-N-hydroxypiperidine-3-carboxamide

The titled compound was prepared using procedures analogous to those inExample 235. MS (ESI): (M+H)⁺=493.

Example 239(3R,4S)-1-[(E)-(cyanoimino)(cyclopropylamino)methyl]-4-[4-(4-cyano-2-methylphenyl)piperazin-1-yl]carbonyl-N-hydroxypiperidine-3-carboxamide

The titled compound was prepared using procedures analogous to those inExample 235. MS (ESI): (M+H)⁺=479.

Example 240(3R,4S)-1-[(E)-azetidin-1-yl)cyanoimino)methyl]-4-[4-(4-cyano-2-methylphenyl)piperazin-1-yl]carbonyl-N-hydroxypiperidine-3-carboxamide

The titled compound was prepared using procedures analogous to those inExample 235. MS (ESI): (M+H)⁺=479.

Example 2411S,2S,5E)-5-benzylidene-N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxamidetrifluoroacetate (salt Part 1.methyl(1S,2S)-5-oxo-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexane-carboxylate

To a stirred solution of(1S,2S)-2-(methoxycarbonyl)-4-oxocyclohexanecarboxylic acid (1.014 g,0.005065 mol) in anhydrous N,N-dimethylformamide (20.0 mL, 0.258 mol) atrt was added (benzotriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphate (2.989 g, 0.005572 mol), 1-phenylpiperazine (1.17mL, 0.00760 mol), followed by N,N-diisopropylethylamine (2.66 mL, 0.0152mol). The reaction mixture was stirred at rt for 15 h. The reaction wasquenched with water (40 mL), extracted with EtOAc (2×). The combinedorganic layers were washed with brine, dried over magnesium sulfate,filtered and concentrated in vacuo. The residue was purified byCombiflash with 40-70% EtOAc/Hex. to give the product as a colorlesssolid (1.299 g, 74% in yield). MS (ESI): (M+H)⁺=345.1.

Part 2.methyl(1S,2S,5E)-5-benzylidene-2-[(4-phenylpiperazin-1-yl)carbonyl]-cyclohexanecarboxylate

To a suspension of benzyltriphenylphosphonium bromide (0.397 g, 0.000880mol) in anhydrous THF (3.0 mL) at rt was added 1.00 M of sodiumbis(trimethylsilyl)amide in tetrahydrofuran (0.880 mL) dropwise. Theresulting orange suspension was stirred at rt for 1 h, a solution ofmethyl(1S,2S)-5-oxo-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxylate(202 mg, 0.000586 mol) in anhydrous THF (3.0 mL) was then added viacannula. The reaction mixture was stirred at rt for 18 h. The reactionwas quenched with water (20 mL), extracted with EtOAc (2×). The combinedorganic layers were washed with brine, dried over sodium sulfate,filtered and concentrated in vacuo. The residue was purified byCombiflash with 20-60% EtOAc/Hex to give the product (141 mg, 57% inyield) as well as the S.M. (50 mg, 25% recovery of S.M.). MS (ESI):(M+H)⁺=419.2.

Part 3.(1S,2S,5E)-5-benzylidene-N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]-cyclohexanecarboxamidetrifluoroacetate (salt)

Preparation of 1.50 M NH₂OH/NaOMe in MeOH: To a stirred suspension ofhydroxylamine hydrochloride (1.404 g, 0.02000 mol) in anhydrous methanol(6.0 mL) at rt was added 4.37 M of sodium methoxide in methanol (6.86mL). The reaction mixture was heated at 55° C. for 5 min, cooled to rt,then to 0° C. Filtration afforded a clear solution assumed to be ca.1.50 M in methanol.

To a stirred solution ofmethyl(1S,2S,5E)-5-benzylidene-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxylate(30.0 mg, 0.0000717 mol) in anhydrous tetrahydrofuran (2.0 mL, 0.025mol) at rt was added the above 1.50 M of hydroxylamine in methanol (1.43mL). The reaction mixture was stirred at rt for 17 h. The reaction wasquenched with saturated aqueous NH4Cl (15 mL), extracted with EtOAc(2×). The combined organic layers were washed with brine, dried oversodium sulfate, filtered and concentrated in vacuo. The residue waspurified by reverse phase HPLC with 5-95% MeCN/H₂O (with 0.05% TFA,pH=2.5) to give the pure product as a colorless solid (18.3 mg, 48% inyield). MS (ESI): (M+H)⁺=420.1.

Example 2421S,2S,5E)-5-(cyclopropylmethylene)-N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxamidetrifluoroacetate (salt

The titled compound was prepared using procedures analogous to those inExample 241. MS (ESI): (M+H)⁺=384.1.

Example 243(1S,2S,5S)-5-benzyl-N,5-dihydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxamidePart 1.(1S,2S,5E)-5-benzylidene-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxylicacid

To a stirred solution ofmethyl(1S,2S,5E)-5-benzylidene-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxylate(116 mg, 0.000277 mol) in tetrahydrofuran (6.0 mL, 0.074 mol) at rt wasadded a solution of lithium hydroxide (102 mg, 0.00416 mol) in water(2.0 mL, 0.11 mol). The resulting cloudy solution was stirred at rt for17 h. LCMS showed that there was only 40% conversion. The reactionmixture was cooled to 0° C., hydrogen peroxide (0.113 mL, 0.00111 mol)was then added. The reaction mixture was stirred at 0° C. for 2 h. LCMSshowed that there was little change. The reaction mixture was thenstirred at rt over the weekend. LCMS showed the reaction was done. Thereaction was quenched with 10% Na₂S₂O₃ (10 mL), acidified with 1 N HCl(5 mL) to pH=4, extracted with EtOAc (2×). The combined organic layerswere washed with brine, dried over magnesium sulfate, filtered andconcentrated in vacuo to give the desired product as a colorless solid.(112 mg, 100% in yield). MS (ESI): (M+H)⁺=405.1.

Part 2.(1S,2S,5S)-5-[(S)-iodo(phenyl)methyl]-2-[4-(4-iodophenyl)piperazin-1-yl]carbonyl-6-oxabicyclo[3.2.1]octan-7-one

To a stirred solution of(1S,2S,5E)-5-benzylidene-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxylicacid (112 mg, 0.000277 mol) in methylene chloride (5.0 mL, 0.078 mol) atrt was added sodium bicarbonate (69.8 mg, 0.000831 mol) and Iodine (211mg, 0.000831 mol). The reaction mixture was stirred at rt for 24 h. LCMSshowed that the reaction was not done. Water (3.0 mL, 0.17 mol) was thenadded, the reaction mixture was stirred at rt for additional 18 h. Thereaction was quenched with 10% Na₂S₂O₃ (20 mL), extracted with EtOAc(2×). The combined organic layers were washed with brine, dried overmagnesium sulfate, filtered and concentrated in vacuo. The residue waspurified by Combiflash with 20-60% EtOAc/Hex to give the desiredproduct. (49.5 mg, 27% in yield). MS (ESI): (M+H)⁺=656.9.

Part 3.(1S,2S,5S)-5-benzyl-2-[(4-phenylpiperazin-1-yl)carbonyl]-6-oxabicyclo[3.2.1]-octan-7-one

To a solution of(1S,2S,5S)-5-[(S)-iodo(phenyl)methyl]-2-[4-(4-iodophenyl)piperazin-1-yl]carbonyl-6-oxabicyclo[3.2.1]octan-7-one(49.0 mg, 0.0000747 mol) in ethyl acetate (5.0 mL, 0.051 mol) in a Parrbottle was added Calcium carbonate (15 mg, 0.00015 mol) and palladium(20 mg, 0.00002 mol) (as 10% Pd/C). The reaction mixture was stirredunder hydrogen at 55 psi for 18 h. The reaction mixture was diluted withEtOAc, filtered through a pad of Celite and washed with EtOAc. Thefiltrate was concentrated in vacuo to give the crude product. (30 mg,100% in yield). MS (ESI): (M+H)⁺=405.1.

Part 4.(1S,2S,5S)-5-benzyl-N,5-dihydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]-cyclohexanecarboxamide

Preparation of 1.50 M NH₂OH/NaOMe in MeOH: To a stirred suspension ofhydroxylamine hydrochloride (1.404 g, 0.02000 mol) in anhydrous methanol(6.0 mL) at rt was added 4.37 M of sodium methoxide in methanol (6.86mL). The reaction mixture was heated at 55° C. for 5 min, cooled to rt,then to 0° C. Filtration afforded a clear solution assumed to be ca.1.50 M in methanol.

To a stirred solution of(1S,2S,5S)-5-benzyl-2-[(4-phenylpiperazin-1-yl)carbonyl]-6-oxabicyclo[3.2.1]-octan-7-one(8.0 mg, 0.020 mmol) in anhydrous methanol (1.0 mL, 0.025 mol) at rt wasadded 1.50 M of hydroxylamine in methanol (0.396 mL). The reactionmixture was stirred at rt for 3 h. The reaction was quenched withsaturated aqueous NH₄Cl (15 mL), extracted with EtOAc (2×). The combinedorganic layers were washed with brine, dried over sodium sulfate,filtered and concentrated in vacuo. The residue was purified by reversephase HPLC with 5-95% MeCN/H₂O (with 0.05% TFA) to give the pure productas a colorless solid (2.3 mg, 26% in yield). MS (ESI): (M+H)⁺=438.1.

Example 2441S,2S,5R)—N,5-dihydroxy-5-phenyl-2-[(4-phenylpiperazin-1-yl)carbonyl]-cyclohexanecarboxamidetrifluoroacetate (salt Part 1.methyl(1S,2S)-5-hydroxy-5-phenyl-2-[(4-phenylpiperazin-1-yl)carbonyl]-cyclohexanecarboxylate

To a stirred solution ofmethyl(1S,2S)-5-oxo-2-[(4-phenylpiperazin-1-yl)carbonyl]-cyclohexanecarboxylate(130.0 mg, 0.0003775 mol) in anhydrous tetrahydrofuran (4.0 mL, 0.049mol) at −78° C. was added 1.00 M of phenylmagnesium bromide intetrahydrofuran (0.755 mL). The reaction mixture was stirred at −78° C.for 1 h, then slowly warmed to −35° C. over 3 h. The reaction wasquenched with saturated aqueous NH₄Cl (20 mL), extracted with EtOAc(2×). The combined organic layers were washed with brine, dried overmagnesium sulfate, filtered and concentrated in vacuo. The residue waspurified by Combiflash with 30-80% EtOAc/Hex to give the product as acolorless solid. (123 mg, 62% in yield). MS (ESI): (M+H)⁺=423.1.

Part 2.(1S,2S,5R)—N,5-dihydroxy-5-phenyl-2-[(4-phenylpiperazin-1-yl)carbonyl]-cyclohexanecarboxamidetrifluoroacetate (salt)

Preparation of 1.50 M NH₂OH/NaOMe in MeOH: To a stirred suspension ofhydroxylamine hydrochloride (1.404 g, 0.02000 mol) in anhydrous methanol(6.0 mL, 0.15 mol) at rt was added 4.37 M of sodium methoxide inmethanol (6.86 mL). The reaction mixture was stirred at rt for 15 min.Filtration afforded a clear solution assumed to be ca. 1.50 M inmethanol.

To a stirred solution ofmethyl(1S,2S,5R)-5-hydroxy-5-phenyl-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxylate(120.0 mg, 0.0002272 mol) in anhydrous tetrahydrofuran (1.0 mL, 0.012mol) at rt was added 1.50 M of hydroxylamine in methanol (3.03 mL). Thereaction mixture was stirred at rt for 3 h. The reaction was quenchedwith saturated aqueous NH4Cl (15 mL), extracted with EtOAc (2×). Thecombined organic layers were washed with brine, dried over sodiumsulfate, filtered and concentrated in vacuo. The residue was purified byreverse phase HPLC with 5-95% MeCN/H₂O (pH=2 with 0.05% TFA) to give thepure product as a colorless solid (69.2 mg, 56% in yield). MS (ESI):(M+H)⁺=424.1.

Example 2451S,2S,5R)-5-benzyl-N,5-dihydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]-cyclohexanecarboxamidetrifluoroacetate (salt

The titled compound was prepared using procedures analogous to those inExample 244. MS (ESI): (M+H)⁺=438.1.

Example 2461S,2S,5R)—N,5-dihydroxy-5-isopropyl-2-[(4-phenylpiperazin-1-yl)carbonyl]-cyclohexanecarboxamidetrifluoroacetate (salt

The titled compound was prepared using procedures analogous to those inExample 244. MS (ESI): (M+H)⁺=390.1.

Example 2471S,2S,5R)-5-cyclopropyl-N,5-dihydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]-cyclohexanecarboxamidetrifluoroacetate (salt

The titled compound was prepared using procedures analogous to those inExample 244. MS (ESI): (M+H)⁺=388.1.

Example 248(2S,3S,5R)-2-[4-(4-cyano-2-methylphenyl)piperidin-1-yl]carbonyl-N-hydroxy-5-(2-oxo-2-pyrrolidin-1-ylethyl)piperidine-3-carboxamide

The titled compound was prepared using procedures analogous to those inExample 11. MS (ESI): (M+H)⁺=482.1.

Example 249isopropyl(5S,6S)-5-[(hydroxyamino)carbonyl]-6-[(4-phenylpiperidin-1-yl)carbonyl]piperidin-3-ylmethylcarbamate

The titled compound was prepared using procedures analogous to those inExample 11. MS (ESI): (M+H)⁺=447.1.

Example 250(1S,2S)—N-hydroxy-2-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]-5-(pyrrolidin-1-ylcarbonyl)cyclohexanecarboxamidePart 1. 1-tert-butyl2-methyl(1S,2S,4S)-4-hydroxycyclohexane-1,2-dicarboxylate

tert-butyl(1S,2S,5S)-7-oxo-6-oxabicyclo[3.2.1]octane-2-carboxylate (5.65g, 25.0 mmol) was suspended in methanol (20 mL). To that suspension wasadded a 25 wt % solution of sodium methoxide in methanol (52 mL) and thereaction mixture was stirred at rt for 2 h. Then it was cooled into anice-water bath and neutralized with a 4 M HCl solution to pH 6. Afterremoving the volatiles, brine was added (50 mL) and the solution wasextracted with ethyl acetate (3×40 mL). The combined organic layers weredried over MgSO₄, filtered and concentrated to provide the desiredproduct (5.70 g, 88.4% yield). LCMS: m/z 281.1 (M+Na)⁺.

Part 2. 1-tert-butyl 2-methyl(1S,2S)-4-oxocyclohexane-1,2-dicarboxylate

The product from Part 1 (6.54 g, 25.3 mmol) was dissolved in acetone (65mL) and cooled to 0° C. Chromium(VI) oxide (2.07 g, 20.7 mmol) wasdissolved in water (6 mL) and to that was added sulfuric acid (1.74 mL)dropwise. The solution was cooled to 0° C. and added dropwise to thesolution above over a period of 10 min. The reaction mixture was stirredat rt for 30 min. Then isopropanol (11 mL) was added and stirring wascontinued for extra 5 min. The reaction mixture was filtered thru asilica gel pad (elution with acetone). Following concentration, ether(60 mL) was added and the solution was washed successively with water(2×50 mL) and brine (50 mL). The organic phase was dried over MgSO₄,filtered and concentrated to provide the desired product as a whitesolid (5.75 g, 88.6% yield).

Part 3. 1-tert-butyl2-methyl(1S,2S,4E)-4-(methoxymethylene)cyclohexane-1,2-dicarboxylate

The product from Part 2 (2.00 g, 7.80 mmol) was dissolved in THF.Chloro(methoxymethyl)triphenylphosphorane (4.01 g, 11.7 mmol) was alsodissolved in THF and cooled to 0° C. To that solution was added a 1.00 Msolution of NaHMDS in THF (11.7 mL) and the reaction mixture was stirredfor 15 min. This Witting reagent was added to the former solution at 0°C. over a period of 25 min. After stirring for 30 min, the reactionmixture was diluted with ethyl acetate (50 mL) and was washedsuccessively with water (2×100 mL) and brine (1×100 mL). The organicphase was dried over MgSO₄, filtered and concentrated. The residue wasflash chromatographed (silica, hexanes:EtOAc, 12:1 to 10:1 to 8:1 to6:1) to provide the desired product as a yellow oil (1.43 g, 64.6%yield).

Part 4. 1-tert-butyl2-methyl(1S,2S)-4-formylcyclohexane-1,2-dicarboxylate

The product from Part 3 (0.510 g, 1.79 mmol) was dissolved inacetonitrile (18.0 mL) and water (4.5 mL) and treated with mercury(II)acetate (2.29 g, 7.17 mmol). The heterogeneous reaction mixture wasstirred at rt overnight. It was diluted with a saturated aqueoussolution of potassium iodide and subsequently extracted with EtOAc. Theorganic phase was washed with brine, dried over MgSO₄, filtered andconcentrated. The residue was flash chromatographed (silica,hexanes:EtOAc, 5:1 to 3:1 to 1:1) to provide the desired aldehyde (0.456g, 94% yield) as a mixture of two isomers (equatorial:axial, 3.5:1,based on ¹H NMR).

Part 5.(3S,4S)-4-(tert-butoxycarbonyl)-3-(methoxycarbonyl)cyclohexanecarboxylicacid

The product from Part 4 (52 mg, 0.192 mmol) was dissolved in DMF (1.9mL) and treated with oxone (118 mg, 0.192 mmol). The reaction mixturewas stirred at rt for 4.5 h. It was diluted with a small volume of a 0.1N HCl solution, followed by EtOAc and water. The layers were separatedand the organic layer was dried over MgSO₄, filtered and concentrated toprovide the desired product as yellow oil (52 mg, 94.4% yield). LCMS:m/z 309.0 (M+Na)⁺.

Part 6. 1-tert-butyl2-methyl(1S,2S)-4-(pyrrolidin-1-ylcarbonyl)cyclohexane-1,2-dicarboxylate

The product from Part 5 (0.265 g, 0.925 mmol) was dissolved in DMF (9.3mL) and treated with BOP reagent (0.491 g, 1.11 mmol). After stirringfor 10 min, pyrrolidine (81.1 μL, 0.971 mmol) was added followed byN,N-diisopropylethylamine (322 μL, 1.85 mmol). The reaction mixture wasstirred at rt overnight. It was poured into a saturated aq. NaHCO₃solution and extracted with EtOAc. The organic phase was washed withwater (2×) and brine, dried over MgSO₄, filtered and concentrated. Theresidue was flash chromatographed (silica, hexanes:EtOAc, 5:1 to 4:1 to3:1) to provide the desired product (0.265 g, 84.4% yield). LCMS: m/z340.1 (M+H)⁺.

Part 7.(1S,2S)-2-(methoxycarbonyl)-4-(pyrrolidin-1-ylcarbonyl)cyclohexanecarboxylicacid

The product from Part 6 (0.260 g, 0.766 mmol) was dissolved indichloromethane (2.7 mL), cooled to 0° C. and treated with TFA (2.74mL). The reaction mixture was stirred at rt for 2 h. Water was addedfollowed by additional dichloromethane, and the layers were separated.The organic phase was dried over MgSO₄, filtered and concentrated. Theresidue was azeotroped with toluene (3×) and dried under high vacuum toprovide the desired product (217 mg, 100% yield). LCMS: m/z 284.2(M+H)⁺.

Part 8.methyl(1S,2S)-2-[(4-phenylpiperidin-1-yl)carbonyl]-5-(pyrrolidin-1-ylcarbonyl)cyclohexanecarboxylate

The product from Part 7 (0.112 g, 0.395 mmol) was dissolved in DMF (4.0mL) and treated with BOP reagent (0.210 g, 0.474 mmol). After stirringfor 10 min, the HCl salt of 4-phenyl-1,2,3,6-tetrahydropyridine (81 mg,0.415 mmol) was added followed by N,N-diisopropylethylamine (206 μL,1.18 mmol). The reaction mixture was stirred at rt overnight. It waspoured into a saturated aq. NaHCO₃ solution and extracted with EtOAc.The organic phase was washed with water (2×) and brine, dried overMgSO₄, filtered and concentrated. The residue was flash chromatographed(silica, hexanes:EtOAc, 5:1 to 4:1 to 3:1) to provide the desiredproduct (0.126 g, 79.7% yield). LCMS: m/z 425.2 (M+H)⁺.

Part 9.(1S,2S)—N-hydroxy-2-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]-5-(pyrrolidin-1-ylcarbonyl)cyclohexanecarboxamide

The product from Part 8 (89 mg, 0.210 mmol) was dissolved in methanol(2.1 mL) and treated with a 1.5 M NH₂OH/NaOMe solution in methanol (2.8mL). (Preparation of a 1.5 M NH₂OH/NaOMe solution in methanol: To astirred suspension of hydroxylamine hydrochloride (1.404 g, 20.20 mmol)in anhydrous methanol (6 mL) at rt was added a 4.37 M solution of sodiummethoxide in methanol (6.86 mL). The reaction mixture was heated at 55°C. for 5 min and then cooled to rt first and then to 0° C. Filtrationthru a filter plug afforded a clear solution assumed to be ca. 1.50 M inmethanol.) The reaction was monitored by LCMS and when complete waspoured into a saturated NH4Cl solution and extracted twice with EtOAc.The combined organic extracts were dried over MgSO₄, filtered andconcentrated. The residue was purified by prep HPLC (reverse phase, 5%MeCN to 95% MeCN in 35 min, pH=2.5) to provide the desired hydroxamicacid (36 mg, 40.4% yield). LCMS: m/z 426.2 (M+H)⁺.

Example 251N-cyclopropyl-N-({(3S,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexyl}methyl)morpholine-4-carboxamidePart 1. 1-tert-butyl2-methyl(1S,2S)-4-[(cyclopropylamino)methyl]cyclohexane-1,2-dicarboxylate

The product from Example 250, Part 4 (174 mg, 0.644 mmol) andcyclopropylamine (35.6 mg, 0.611 mmol) were dissolved in methanol (6.0mL). That solution was treated with acetic acid (0.209 mL) and sodiumcyanoborohydride (38.4 mg, 0.611 mmol). The reaction mixture was stirredat rt overnight. It was concentrated, diluted with ethyl acetate andwashed with a saturated NaHCO₃ solution. The organic layer was driedover MgSO₄, filtered and concentrated. The residue was flashchromatographed (silica, 5% to 6% to 10% MeOH/CH₂Cl₂) to provide thedesired product as a colorless oil (131 mg, 68.8% yield). LCMS: m/z312.2 (M+H)⁺.

Part 2. 1-tert-butyl2-methyl(1S,2S)-4-{[cyclopropyl(morpholin-4-ylcarbonyl)amino]methyl}cyclohexane-1,2-dicarboxylate

The product from Part 1 (131 mg, 0.421 mmol) was dissolved indichloromethane (4.2 mL) and cooled to 0° C. That solution was treatedsuccessively with N,N-diisopropylethylamine (0.146 mL, 0.841 mmol) andmorpholine-4-carbonyl chloride (54 μL, 0.463 mmol). The reaction mixturewas stirred at rt for 36 hrs. It was diluted with dichloromethane andpoured into a 0.1 M HCl solution. The layers were separated and theorganic phase was dried over MgSO₄, filtered and concentrated. Theresidue was flash chromatographed (silica, 2% MeOH/CH₂Cl₂) to providethe desired product as a colorless oil (0.148 g, 82.9% yield). LCMS: m/z425.2 (M+H)⁺.

Part 3.(1S,2S)-4-{[cyclopropyl(morpholin-4-ylcarbonyl)amino]methyl}-2-(methoxycarbonyl)cyclohexanecarboxylicacid

The procedure described in Example 250, Part 7 was followed to providethe desired carboxylic acid (0.124 g, 96.5% yield). LCMS: m/z 369.1(M+H)⁺.

Part 4.Methyl(1S,2S)-5-{[cyclopropyl(morpholin-4-ylcarbonyl)amino]methyl}-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxylate

According to the procedure described in Example 250, Part 8 and using1-phenylpiperazine, the desired product was obtained (0.140 g, 81.1%yield). LCMS: m/z 513.3 (M+H)⁺.

Part 5.N-cyclopropyl-N-({(3S,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexyl}methyl)morpholine-4-carboxamide

Using the procedure described in Example 250, Part 9, the desiredproduct was obtained (56 mg, 46% yield). LCMS: m/z 514.3 (M+H)⁺.

Example 252(1S,2S,5S)—N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]-5-(piperidin-1-ylcarbonyl)cyclohexanecarboxamide

This compound was prepared according to Example 250. LCMS: m/z 443.1(M+H)⁺.

Example 253(1S,2S,5R)—N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]-5-(piperidin-1-ylcarbonyl)cyclohexanecarboxamide

This compound was prepared according to Example 250. LCMS: m/z 443.1(M+H)⁺.

Example 254(1S,2S,5S)—N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]-5-(pyrrolidin-1-ylcarbonyl)cyclohexanecarboxamide

This compound was prepared according to Example 250. LCMS: m/z 429.1(M+H)⁺.

Example 255(1S,2S,5R)—N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]-5-(pyrrolidin-1-ylcarbonyl)cyclohexanecarboxamide

This compound was prepared according to Example 250. LCMS: m/z 429.1(M+H)⁺.

Example 256(1S,2S)—N-hydroxy-5-(morpholin-4-ylcarbonyl)-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxamide

It was prepared according to Example 250. LCMS: m/z 445.2 (M+H)⁺.

Example 257N-cyclopentyl-N-({(3S,4S,5S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexyl}methyl)piperidine-1-carboxamide

This compound was prepared according to Example 251. LCMS: m/z 540.2(M+H)⁺.

Example 258N-cyclopentyl-N-({(3S,4S,5R)-3-[(hydroxyamino)carbonyl]-4-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexyl}methyl)piperidine-1-carboxamide

This compound was prepared according to Example 251. LCMS: m/z 540.2(M+H)⁺.

Example 259(1R,3S,4S)-3-[(hydroxyamino)carbonyl]-4-{[(3R)-3-phenylpyrrolidin-1-yl]carbonyl}cyclohexylpyrrolidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 72. MS (ESI): (M+H)⁺=430.1.

Example 260(1R,3S,4S)-3-[(hydroxyamino)carbonyl]-4-{[(3R)-3-phenylpyrrolidin-1-yl]carbonyl}cyclohexyldimethylcarbamate

This compound was prepared using procedures analogous to those forexample 72. MS (ESI): (M+H)⁺=404.1.

Example 261(1R,3S,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]cyclohexylmorpholine-4-carboxylate

This compound was prepared using procedures analogous to those forexample 72. MS (ESI): (M+H)⁺=458.1.

Example 262(1R,3S,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]cyclohexylpyrrolidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 72. MS (ESI): (M+H)⁺=442.1.

Example 263(1R,3S,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]cyclohexylmethylcarbamate

This compound was prepared using procedures analogous to those forexample 72. MS (ESI): (M+H)⁺=402.1.

Example 264(1R,3S,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]cyclohexyldimethylcarbamate

This compound was prepared using procedures analogous to those forexample 72. MS (ESI): (M+H)⁺=416.1.

Example 265(1S,2S,5R)—N,5-dihydroxy-2-{[(3R)-3-phenylpyrrolidin-1-yl]carbonyl}cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 72. MS (ESI): (M+H)⁺=333.1.

Example 266(1S,3S,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]cyclohexyldimethylcarbamate

This compound was prepared using procedures analogous to those forexample 72. MS (ESI): (M+H)⁺=416.1.

Example 267(1S,3S,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]cyclohexylpyrrolidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 72. MS (ESI): (M+H)⁺=442.1.

Example 268(1S,3S,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]cyclohexylmethylcarbamate

This compound was prepared using procedures analogous to those forexample 72. MS (ESI): (M+H)⁺=402.1.

Example 269(1S,3S,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]cyclohexylmorpholine-4-carboxylate

This compound was prepared using procedures analogous to those forexample 72. MS (ESI): (M+H)⁺=458.1.

Example 270(1R,3S,4S)-3-[(hydroxyamino)carbonyl]-4-{[(3R)-3-phenylpyrrolidin-1-yl]carbonyl}cyclohexylmethylcarbamate

This compound was prepared using procedures analogous to those forexample 72. MS (ESI): (M+H)⁺=390.1.

Example 271(1R,3S,4S)-3-[(hydroxyamino)carbonyl]-4-{[(3R)-3-phenylpyrrolidin-1-yl]carbonyl}cyclohexylmorpholine-4-carboxylate

This compound was prepared using procedures analogous to those forexample 72. MS (ESI): (M+H)⁺=446.1.

Example 272(1R,3S,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenylpiperidin-1-yl)carbonyl]cyclohexylpyrrolidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 72. MS (ESI): (M+H)⁺=444.2.

Example 273(1R,3S,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexylpiperidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 72. MS (ESI): (M+H)⁺=459.2.

Example 274(1R,3S,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexylpyrrolidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 72. MS (ESI): (M+H)⁺=445.2.

Example 275(1R,3S,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexyldimethylcarbamate

This compound was prepared using procedures analogous to those forexample 72. MS (ESI): (M+H)⁺=419.2.

Example 276(1R,3S,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexylmethylcarbamate

This compound was prepared using procedures analogous to those forexample 72. MS (ESI): (M+H)⁺=405.2.

Example 277(1R,3S,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]cyclohexylpyrrolidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 72. MS (ESI): (M+H)⁺=442.2.

Example 278(1R,3S,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]cyclohexylmethylcarbamate

This compound was prepared using procedures analogous to those forexample 72. MS (ESI): (M+H)⁺=402.1.

Example 279(1R,3S,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]cyclohexyldimethylcarbamate

This compound was prepared using procedures analogous to those forexample 72. MS (ESI): (M+H)⁺=416.1.

Example 280(1R,3S,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenylpiperidin-1-yl)carbonyl]cyclohexyldimethylcarbamate

This compound was prepared using procedures analogous to those forexample 72. MS (ESI): (M+H)⁺=418.2

Example 281(1R,3S,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenylpiperidin-1-yl)carbonyl]cyclohexylpiperidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 72. MS (ESI): (M+H)⁺=458.2

Example 282(1S,2S,5R)—N,5-dihydroxy-5-methyl-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 243. MS (ESI): (M+H)⁺=362.1.

Example 283(1S,2S,5S)—N,5-dihydroxy-5-methyl-2-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 243. MS (ESI): (M+H)⁺=359.1.

Example 284(1R,3R,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexyl(3R)-3-hydroxypyrrolidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 72. MS (ESI): (M+H)⁺=461.2.

Example 285N-{(1R,3S,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexyl}-azetidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 72.

Example 286(1R,3S,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexyldiethylcarbamate

This compound was prepared using procedures analogous to those forexample 72. MS (ESI): (M+H)⁺=447.2.

Example 287(1S,2S,5R)-5-allyl-N,5-dihydroxy-2-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 243. MS (ESI): (M+H)⁺=385.2.

Example 288(1S,2S,5R)-5-allyl-N,5-dihydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 243. MS (ESI): (M+H)⁺=388.2.

Example 289(1S,2S,5S)-5-allyl-N,5-dihydroxy-2-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 243. MS (ESI): (M+H)⁺=385.2.

Example 290(1S,2S,5S)-5-allyl-N,5-dihydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 243. MS (ESI): (M+H)⁺=388.2.

Example 291(1S,2S,5R)—N,5-dihydroxy-5-methyl-2-[(4-phenylpiperidin-1-yl)carbonyl]cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 243. MS (ESI): (M+H)⁺=361.2.

Example 292(1S,2S,5S)—N,5-dihydroxy-5-methyl-2-[(4-phenylpiperidin-1-yl)carbonyl]cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 243. MS (ESI): (M+H)⁺=361.2.

Example 293(1S,2S,5S)—N,5-dihydroxy-5-methyl-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 243. MS (ESI): (M+H)⁺=362.2.

Example 294(1S,2S,5R)—N,5-dihydroxy-2-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]-5-propylcyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 243.

Example 295(1S,2S,5S)—N,5-dihydroxy-2-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]-5-propylcyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 243.

Example 296(1S,2S,5R)—N-hydroxy-5-phenoxy-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxamidePart 1.(1S,2S,5S)-2-[(4-phenylpiperazin-1-yl)carbonyl]-6-oxabicyclo[3.2.1]octan-7-one

Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(7.0 g, 0.016 mol) was added To a solution of(1S,2S,5S)-7-oxo-6-oxabicyclo[3.2.1]octane-2-carboxylic acid (14.4 mmol,0.0144 mol) and 1-Phenylpiperazine (2.4 mL, 0.016 mol) inN,N-dimethylformamide (30 mL, 0.4 mol) at 0 Celsius. After 5 minutes,N,N-diisopropylethylamine (7.5 mL, 0.043 mol) was added at 0 Celsius.The mixture was stirred at RT for overnight. The product was purified byflash chromatography on silica gel column (ethyl acetate in hexanes:60%).

Part 2.Methyl(1S,2S,5R)-5-phenoxy-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexane-carboxylate

Triphenylphosphine (150 mg, 0.00058 mol) was added To a solution ofmethyl(1S,2S,5S)-5-hydroxy-2[(4-phenylpiperazin-1-yl)carbonyl]cyclohexane-carboxylate(100.0 mg, 0.00029 mol) and phenol (54 mg, 0.00058 mol) intetrahydrofuran (2.0 mL) at RT under nitrogen. A solution of diethylazodicarboxylate (91 uL, 0.00058 mol) in tetrahydrofuran (2.0 mL) wasadded. The reaction mixture was stirred at RT for overnight. The productwas purified by flash chromatography on silica gel column (ethyl acetatein hexanes: 30%).

Part 3.(1S,2S,5R)—N-hydroxy-5-phenoxy-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxamide

A solution of hydroxyamine in MeOH (1.5 M, 0.75 ml) was added tomethyl(1S,2S,5R)-5-phenoxy-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexane-carboxylate(0.29 mmol, 0.00029 mol) in MeOH (0.5 mL) at RT. The resulting mixturewas stirred at RT for 2 hrs, and was adjusted to PH=2.0 with TFA, andthen was purified by Prep-HPLC to give the desired product. LCMS:(M+H)⁺=424.2.

Example 297(1S,2S,5R)—N-hydroxy-5-[(6-methylpyridin-3-yl)oxy]-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 296. LCMS: (M+H)⁺=439.2.

Example 298(1S,2S,5R)—N-hydroxy-5-(4-methylphenoxy)-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 296. LCMS: (M+H)⁺=438.1.

Example 299(1S,2S,5R)-5-(2,3-difluorophenoxy)-N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 296. LCMS: (M+H)⁺=460.2.

Example 300(1S,2S,5R)—N-hydroxy-5-[(6-methylpyridin-2-yl)oxy]-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 296. LCMS: (M+H)⁺=439.2.

Example 301(1S,2S,5R)—N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]-5-[(2-methylquinolin-4-yl)oxy]cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 296. LCMS: (M+H)⁺=489.2.

Example 302(1S,2S,5R)-5-(3,4-difluorophenoxy)-N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 296. LCMS: (M+H)⁺=460.2.

Example 303(1S,2S,5R)-5-[(5-chloropyridin-3-yl)oxy]-N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 296. LCMS: (M+H)⁺=459.1/461.1.

Example 304(1S,2S,5R)—N-hydroxy-5-[1-(methylsulfonyl)piperidin-4-yl]oxy-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 317. LCMS: (M+H)⁺=509.0

Example 305(1S,2S,5R)-5-(2,4-dichlorophenoxy)-N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 296. LCMS: (M+H)⁺=492.1/494.1.

Example 306 methyl4-01R,3S,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexyloxy)piperidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 317. LCMS: (M+H)⁺=489.1.

Example 307(1S,2S,5R)—N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]-5-(pyridin-3-yloxy)cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 296. LCMS: (M+H)⁺=425.1.

Example 308(1S,2S,5R)-5-(4-fluorophenoxy)-N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 296. LCMS: (M+H)⁺=442.2.

Example 309(1S,2S,5R)-5-[(1-ethylpiperidin-4-yl)oxy]-N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 317. LCMS: (M+H)⁺=459.2.

Example 310(1S,2S,5R)-5-[(1-ethylpiperidin-4-yl)oxy]-N-hydroxy-2-[(3-phenyl-2,5-dihydro-1H-pyrrol-1-yl)carbonyl]cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 317. LCMS: (M+H)⁺=442.2

Example 311(1S,2S,5R)—N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]-5-(quinolin-6-yloxy)cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 296. LCMS: (M+H)⁺=475.2.

Example 312(1S,2S,5R)-5-(2,3-dichlorophenoxy)-N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 296. LCMS: (M+H)⁺=492.0/494.0.

Example 313(1S,2S,5R)-5-(benzyloxy)-N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 296. LCMS: (M+H)⁺=438.2.

Example 314(1S,2S,5R)—N-hydroxy-5-[(4-methylpyridin-2-yl)oxy]-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 296. LCMS: (M+H)⁺=439.2.

Example 315(1S,2S,5R)-5-(3-fluorophenoxy)-N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 296. LCMS: (M+H)⁺=442.2.

Example 316(1S,2S,5R)—N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]-5-(pyridin-4-yloxy)cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 296. LCMS: (M+H)⁺=425.2.

Example 317(1S,2S,5R)-5-[(1-acetylpiperidin-4-yl)oxy]-N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxamide

Triphenylphosphine (2.0E3 mg, 0.0077 mol) was added To a solution of1-tert-butyl 2-methyl(1S,2S,4S)-4-hydroxycyclohexane-1,2-dicarboxylate(1.0 g, 0.0039 mol) and 4-pyridinol (730 mg, 0.0076 mol) intetrahydrofuran (10.0 mL, 0.123 mol) at rt. A solution of diethylazodicarboxylate (1200 uL, 0.0077 mol) in tetrahydrofuran (10.0 mL,0.123 mol) was added. The reaction mixture was stirred at rt overnight.The reaction was chromatographed by combiflash (ethyl acetate inhexanes: 80%) to give 1-tert-butyl2-methyl(1S,2S,4R)-4-(pyridin-4-yloxy)cyclohexane-1,2-dicarboxylate,contaminated with a little Ph₃PO, which was used in next step.

20 mg of Pd black and 1 ml of 1M HCl in ether was added a solution of1-tert-butyl2-methyl(1S,2S,4R)-4-(pyridin-4-yloxy)cyclohexane-1,2-dicarboxylate (0.1g, 0.0003 mol) in methanol (50 mL, 1 mol). The reaction was shaken underan atmosphere of hydrogen (60 Psi) overnight. LCMS showed the reactionwas complete.

A solution of acetyl chloride (24 uL, 0.00033 mol) in 0.5 ml of ACN wasadded to a solution of 1-tert-butyl2-methyl(1S,2S,4R)-4-(piperidin-4-yloxy)cyclohexane-1,2-dicarboxylatehydrochloride made above (50 mg, 0.0001 mol) and 4-methylmorpholine (44uL, 0.00040 mol) in acetonitrile (1.5 mL, 0.029 mol) at 22 Celsius. Itwas stirred at rt for 30 min, then quenched with Water, extracted withEA, and concentrated to give 1-tert-butyl2-methyl(1S,2S,4R)-4-[(1-acetylpiperidin-4-yl)oxy]cyclohexane-1,2-dicarboxylate.2 ml of TFA was added in 1-tert-butyl2-methyl(1S,2S,4R)-4-[(1-acetylpiperidin-4-yl)oxy]cyclohexane-1,2-dicarboxylate(0.1 mmol, 0.0001 mol) in dichloromethane (2 ml). It was stirred at rtovernight and concentrated to give the corresponding TFA salt for nextstep. Benzotriazol-1-yloxytris(dimethylamino)-phosphoniumhexafluorophosphate (49 mg, 0.00011 mol) was added To a solution of(1S,2S,4R)-4-[(1-acetylpiperidin-4-yl)oxy]-2-(methoxycarbonyl)cyclohexanecarboxylicacid made above (0.1 mmol, 0.0001 mol) and 1-phenylpiperazine (17 uL,0.00011 mol) in N,N-dimethylformamide (0.5 mL, 0.006 mol) at rt. After 5min, N,N-diisopropylethylamine (52 uL, 0.00030 mol) was added at 0Celsius. It was stirred at rt overnight. The reaction waschromatographed by combiflash (ethyl acetate in hexanes: 100%).

1.5 M of H₂NOH in MeOH (0.75 ml) was added inTo a solution ofmethyl(1S,2S,5R)-5-[(1-acetylpiperidin-4-yl)oxy]-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexane-carboxylate(0.1 mmol, 0.0001 mol) in 0.5 ml of MeOH. It was stirred at rt for 2hrs. It was purified by Prep-HPLC. LCMS: (M+H)⁺=473.1.

Example 318(1S,2S,5R)—N-hydroxy-5-[(2-methylpyridin-3-yl)oxy]-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 296. LCMS: (M+H)⁺=439.2.

Example 319(1S,2S,5R)-5-[3,5-bis(trifluoromethyl)phenoxy]-N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 296. LCMS: (M+H)⁺=560.2.

Example 320(1S,2S,5R)-5-(2-chlorophenoxy)-N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 296. LCMS: (M+H)⁺=458.1/460.1.

Example 321(1S,2S,5R)-5-(4-chlorophenoxy)-N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 296. LCMS: (M+H)⁺=458.2/460.1.

Example 322(1S,2S,5R)-5-(3-bromophenoxy)-N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 296. LCMS: (M+H)⁺=502.1/504.1.

Example 323(1S,2S,5R)-5-(1,3-benzothiazol-2-yloxy)-N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 296. LCMS: (M+H)⁺=481.1.

Example 324(1S,2S,5R)-5-(3-chlorophenoxy)-N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 296.

Example 325(1S,2S,5R)—N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]-5-(pyrimidin-2-yloxy)cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 296. LCMS: (M+H)⁺=426.2.

Example 326(1S,2S,5R)—N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]-5-[3-(trifluoromethyl)phenoxy]cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 296. LCMS: (M+H)⁺=492.1.

Example 327(1S,2S,5R)—N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]-5-(quinolin-4-yloxy)cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 296. LCMS: (M+H)⁺=475.2.

Example 328(1S,2S,5R)—N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]-5-(thieno[3,2-b]pyridin-7-yloxy)cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 296. LCMS: (M+H)⁺=481.2.

Example 329(1S,2S,5R)—N-hydroxy-5-[isobutyryl(methyl)amino]-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 72. LCMS: (M+H)⁺=431.3

Example 330(1R,3S,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenylpiperidin-1-yl)carbonyl]cyclohexylcyclopropylcarbamate

This compound was prepared using procedures analogous to those forexample 72. LCMS: (M+H)⁺=430.2

Example 331(1R,3S,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenylpiperidin-1-yl)carbonyl]cyclohexylethylcarbamate

This compound was prepared using procedures analogous to those forexample 72. LCMS: (M+H)⁺=418.1

Example 332(1R,3S,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenylpiperidin-1-yl)carbonyl]cyclohexylmethylcarbamate

This compound was prepared using procedures analogous to those forexample 72. LCMS: (M+H)⁺=404.1

Example 333(1R,3S,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenylpiperidin-1-yl)carbonyl]cyclohexylisopropylcarbamate

This compound was prepared using procedures analogous to those forexample 72. LCMS: (M+H)⁺=432.1

Example 334(1R,3S,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenylpiperidin-1-yl)carbonyl]cyclohexylprop-2-yn-1-ylcarbamate

This compound was prepared using procedures analogous to those forexample 72. LCMS: (M+H)⁺=428.1

Example 335(1R,3S,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenylpiperidin-1-yl)carbonyl]cyclohexylpiperidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 72.

Example 336(1R,3S,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenylpiperidin-1-yl)carbonyl]cyclohexyl4-methylpiperazine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 72. LCMS: (M+H)⁺=473.2

Example 337(1R,3S,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenylpiperidin-1-yl)carbonyl]cyclohexylcarbamate

This compound was prepared using procedures analogous to those forexample 72. LCMS: (M+H)⁺=390.2

Example 338(1R,3S,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexyl(1-methylpiperidin-4-yl)carbamate

This compound was prepared using procedures analogous to those forexample 72. LCMS: (M+H)⁺=488.3

Example 339(1R,3S,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexylisobutyl(methyl)carbamate

This compound was prepared using procedures analogous to those forexample 72. LCMS: (M+H)⁺=461.2

Example 340(1R,3S,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexylmethyl(3-phenylpropyl)carbamate

This compound was prepared using procedures analogous to those forexample 72. LCMS: (M+H)⁺=523.3

Example 341(1R,3S,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexylcyclohexyl(methyl)carbamate

This compound was prepared using procedures analogous to those forexample 72. LCMS: (M+H)⁺=487.3

Example 342(1R,3S,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexyl(4-methoxyphenyl)methylcarbamate

This compound was prepared using procedures analogous to those forexample 72. LCMS: (M+H)⁺=511.3

Example 343(1R,3S,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexylindoline-1-carboxylate

This compound was prepared using procedures analogous to those forexample 72. LCMS: (M+H)⁺=493.2

Example 344(1R,3S,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexyl1,3-dihydro-2H-isoindole-2-carboxylate

This compound was prepared using procedures analogous to those forexample 72. LCMS: (M+H)⁺=493.2

Example 345(1R,3S,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexyl(2-phenylcyclopropyl)carbamate

This compound was prepared using procedures analogous to those forexample 72. LCMS: (M+H)⁺=507.3

Example 346(1R,3S,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexylcyclobutylcarbamate

This compound was prepared using procedures analogous to those forexample 72. LCMS: (M+H)⁺=445.2

Example 347 ethyl4-{[({(1R,3S,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexyl}oxy)carbonyl]amino}piperidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 72. LCMS: (M+H)⁺=546.3

Example 348(1R,3S,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexyltetrahydrofuran-3-ylcarbamate

This compound was prepared using procedures analogous to those forexample 72. LCMS: (M+H)⁺=461.2

Example 349(1R,3S,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexyl(4-hydroxycyclohexyl)carbamate

This compound was prepared using procedures analogous to those forexample 72. LCMS: (M+H)⁺=489.2

Example 350(1R,3S,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexyl(2-methoxyethyl)carbamate

This compound was prepared using procedures analogous to those forexample 72. LCMS: (M+H)⁺=449.2

Example 351(1R,3S,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexyl(pyridin-2-ylmethyl)carbamate

This compound was prepared using procedures analogous to those forexample 72. LCMS: (M+H)⁺=482.2

Example 352(1R,3S,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexyl(pyridin-3-ylmethyl)carbamate

This compound was prepared using procedures analogous to those forexample 72. LCMS: (M+H)⁺=482.2

Example 353(1R,3S,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexyl(pyridin-4-ylmethyl)carbamate

This compound was prepared using procedures analogous to those forexample 72. LCMS: (M+H)⁺=482.2

Example 354(1R,3S,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexyl2,5-dihydro-1H-pyrrole-1-carboxylate

This compound was prepared using procedures analogous to those forexample 72.

Example 355(1R,3S,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexylcyclopentylcarbamate

This compound was prepared using procedures analogous to those forexample 72. LCMS: (M+H)⁺=459.2

Example 356(1R,3S,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexylcyclohexylcarbamate

This compound was prepared using procedures analogous to those forexample 72. LCMS: (M+H)⁺=473.3

Example 357ethyl(1R,3S,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexylpiperazine-1,4-dicarboxylate

This compound was prepared using procedures analogous to those forexample 72. LCMS: (M+H)⁺=532.3

Example 358(1R,3S,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexyl4-{2-[methyl(phenyl)amino]-2-oxoethyl}piperazine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 72. LCMS: (M+H)⁺=607.3

Example 359(1R,3S,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexyl4-hydroxypiperidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 72. LCMS: (M+H)⁺=475.2

Example 360(1R,3S,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexyl(3R)-3-(acetylamino)pyrrolidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 72. LCMS: (M+H)⁺=502.3

Example 361(1R,3S,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexyl(3S)-3-(acetylamino)pyrrolidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 72. LCMS: (M+H)⁺=502.2

Example 362(1R,3S,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexyl(2R)-2-(hydroxymethyl)pyrrolidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 72. LCMS: (M+H)⁺=475.2

Example 363(1R,3S,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexyl(2S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 72. LCMS: (M+H)⁺=475.2

Example 364(1R,3S,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexyl[1-(hydroxymethyl)cyclopentyl]carbamate

This compound was prepared using procedures analogous to those forexample 72. LCMS: (M+H)⁺=489.3

Example 365(1R,3S,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexyl[(1R,2R)-2-hydroxycyclopentyl]carbamate

This compound was prepared using procedures analogous to those forexample 72. LCMS: (M+H)⁺=475.2

Example 366(1R,3S,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexyl[2-(hydroxymethyl)cyclohexyl]carbamate

This compound was prepared using procedures analogous to those forexample 72. LCMS: (M+H)⁺=503.3

Example 367(1R,3S,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexyl[(2R)-2-hydroxycyclohexyl]carbamate

This compound was prepared using procedures analogous to those forexample 72. LCMS: (M+H)⁺=489.3

Example 368(1R,3S,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexyl[(1R)-2-hydroxy-1-phenylethyl]carbamate

This compound was prepared using procedures analogous to those forexample 72. LCMS: (M+H)⁺=511.2

Example 369(1R,3S,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexyl[(1R)-2-hydroxy-1-methylethyl]carbamate

This compound was prepared using procedures analogous to those forexample 72. LCMS: (M+H)⁺=449.2

Example 370(1R,3S,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexyl[(1R)-1-(hydroxymethyl)propyl]carbamate

This compound was prepared using procedures analogous to those forexample 72. LCMS: (M+H)⁺=463.2

Example 371(1R,3S,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexyl[(1R)-1-(hydroxymethyl)-2-methylpropyl]carbamate

This compound was prepared using procedures analogous to those forexample 72. LCMS: (M+H)⁺=477.2

Example 372(1R,3S,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexyl[(2R)-2-hydroxypropyl]carbamate

This compound was prepared using procedures analogous to those forexample 72. LCMS: (M+H)⁺=449.2

Example 373(1R,3S,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexyl(3-hydroxy-1-phenylpropyl)carbamate

This compound was prepared using procedures analogous to those forexample 72. LCMS: (M+H)⁺=525.3

Example 374(1R,3S,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexyl[(1R)-1-(hydroxymethyl)-3-methylbutyl]carbamate

This compound was prepared using procedures analogous to those forexample 72. LCMS: (M+H)⁺=491.2

Example 375(1R,3S,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexyl4-formylpiperazine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 72. LCMS: (M+H)⁺=488.2

Example 376(1S,2S,5R)—N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]-5-(pyridin-3-ylmethoxy)cyclohexanecarboxamide

1.00 M of Potassium tert-butoxide in tetrahydrofuran (0.212 mL) wasadded to a mixture ofmethyl(1S,2S,5R)-5-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxylate(36.8 mg, 0.000106 mol) and 3-chloromethylpyridine hydrochloride (17.4mg, 0.106 mmol) in tetrahydrofuran (1.0 mL, 0.012 mol) at 0 Celsius. Themixture was stirred at room temperature for 1 hr then purified by HPLC.1.5 M of hydroxyamine solution (0.7 ml) was added into to a solution ofmethyl(1S,2S,5R)-2-[(4-phenylpiperazin-1-yl)carbonyl]-5-(pyridin-3-ylmethoxy)cyclohexanecarboxylate(0.075 mmol, 0.000075 mol) made above in methanol (0.5 mL, 0.01 mol). Itwas stirred at rt for 2 hrs then purified by Prep-HPLC.

Example 377(1S,2S,5R)—N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]-5-(pyridin-2-yloxy)cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 296. LCMS: (M+H)⁺=425.2

Example 378(1S,2S,5R)—N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]-5-(quinolin-6-yloxy)cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 296. LCMS: (M+H)⁺=475.2

Example 379(1S,2S,5R)-5-[(1-ethylpiperidin-4-yl)oxy]-N-hydroxy-2-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 317.

Example 380(1S,2S,5R)—N-hydroxy-5-(4-hydroxyphenoxy)-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 296. LCMS: (M+H)⁺=440.1

Example 381(1S,2S,5R)—N-hydroxy-5-[(4-methoxycyclohexyl)oxy]-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 317. LCMS: (M+H)⁺=460.2

Example 383(1S,2S,5R)—N-hydroxy-5-[(4-methoxycyclohexyl)oxy]-2-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 317. LCMS: (M+H)⁺=457.2

Example 384(1S,2S,5R)—N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]-5-{[2-(trifluoromethyl)quinolin-4-yl]oxy}cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 296. LCMS: (M+H)⁺=543.2

Example 385(1S,2S,5R)—N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]-5-(quinolin-2-yloxy)cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 296. LCMS: (M+H)⁺=475.2

Example 386(1S,2S,5R)—N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]-5-(quinolin-3-yloxy)cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 296. LCMS: (M+H)⁺=475.1

Example 387(1S,2S,5R)—N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]-5-(quinolin-5-yloxy)cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 296. LCMS: (M+H)⁺=475.1

Example 388(1S,2S,5R)—N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]-5-(quinolin-7-yloxy)cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 296. LCMS: (M+H)⁺=475.2

Example 389(1S,2S,5R)—N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]-5-(quinolin-8-yloxy)cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 296. LCMS: (M+H)⁺=475.1

Example 390(1S,2S,5R)—N-hydroxy-2-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]-5-(pyridin-2-yloxy)cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 296. LCMS: (M+H)⁺=422.1

Example 391(1S,2S,5R)—N-hydroxy-2-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]-5-(pyridin-4-yloxy)cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 296. LCMS: (M+H)⁺=422.1

Example 392(1S,2S,5R)—N-hydroxy-2-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]-5-(quinolin-6-yloxy)cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 296. LCMS: (M+H)⁺=472.1

Example 393(1S,2S,5R)-5-[(1-ethylpiperidin-4-yl)oxy]-N-hydroxy-2-[(4-phenylpiperidin-1-yl)carbonyl]cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 317. LCMS: (M+H)⁺=458.3

Example 394(1S,2S,5R)—N-hydroxy-2-[(4-phenylpiperidin-1-yl)carbonyl]-5-(pyridin-2-yloxy)cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 296. LCMS: (M+H)⁺=424.2

Example 395(1S,2S,5R)—N-hydroxy-2-[(4-phenylpiperidin-1-yl)carbonyl]-5-(pyridin-4-yloxy)cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 296. LCMS: (M+H)⁺=424.2

Example 396(1S,2S,5R)—N-hydroxy-2-[(4-phenylpiperidin-1-yl)carbonyl]-5-(quinolin-6-yloxy)cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 296. LCMS: (M+H)⁺=474.2

Example 397(1S,2S,5R)-5-(3-chlorophenoxy)-N-hydroxy-2-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 296. LCMS: (M+H)⁺=455.1, 457.1

Example 398(1S,2S,5R)-5-(3,4-difluorophenoxy)-N-hydroxy-2-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 296. LCMS: (M+H)⁺=457.1

Example 399(1S,2S,5R)-5-(2,3-difluorophenoxy)-N-hydroxy-2-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 296. LCMS: (M+H)⁺=457.1

Example 400(1S,2S,5R)—N-hydroxy-5-(isoquinolin-1-yloxy)-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 296. LCMS: (M+H)⁺=475.2

Example 401(1S,2S,5R)—N-hydroxy-5-(isoquinolin-3-yloxy)-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 296. LCMS: (M+H)⁺=475.2

Example 402(1S,2S,5R)—N-hydroxy-5-(isoquinolin-5-yloxy)-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 296. LCMS: (M+H)⁺=475.2

Example 403(1S,2S,5R)—N-hydroxy-5-(isoquinolin-7-yloxy)-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 296. LCMS: (M+H)⁺=475.2

Example 404(1S,2S,5R)—N-hydroxy-5-(2-naphthyloxy)-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 296. LCMS: (M+H)⁺=474.2

Example 405(1S,2S,5R)-5-(2,4-difluorophenoxy)-N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 296. LCMS: (M+H)⁺=460.1

Example 406(1S,2S,5R)-5-(3,5-difluorophenoxy)-N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 296. LCMS: (M+H)⁺=460.1

Example 407(1S,2S,5R)-5-(3-chloro-4-fluorophenoxy)-N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 296. LCMS: (M+H)⁺=476.1, 478.1

Example 408(1S,2S,5R)-5-(3,4-dichlorophenoxy)-N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 296. LCMS: (M+H)⁺=492.1, 494.1

Example 409(1S,2S,5R)-5-(3,5-dichlorophenoxy)-N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 296. LCMS: (M+H)⁺=492.1, 494.1

Example 410(1S,2S,5R)-5-(2,5-dioxopyrrolidin-1-yl)-N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 296. LCMS: (M+H)⁺=429.2

Example 411(1S,2S,5R)-5-(5,5-dimethyl-2,4-dioxo-1,3-oxazolidin-3-yl)-N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 296. LCMS: (M+H)⁺=459.2

Example 412(1S,2S,5R)—N-hydroxy-5-(3-methyl-2,5-dioxoimidazolidin-1-yl)-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 296.

Example 413(3S,5S,6S)-5-[(hydroxyamino)carbonyl]-1-methyl-6-[(4-phenylpiperazin-1-yl)carbonyl]piperidin-3-yl2,5-dihydro-1H-pyrrole-1-carboxylate

This compound was prepared using procedures analogous to those forexample 204. MS (ESI) (M+H) 458.1.

Example 414(3S,5S,6S)-5-[(hydroxyamino)carbonyl]-1-methyl-6-[(4-phenylpiperazin-1-yl)carbonyl]piperidin-3-ylazepane-1-carboxylate

This compound was prepared using procedures analogous to those forexample 204. MS (ESI) (M+H) 488.1

Example 415(3S,5S,6S)-5-[(hydroxyamino)carbonyl]-1-methyl-6-[(4-phenylpiperazin-1-yl)carbonyl]piperidin-3-yldimethylcarbamate

This compound was prepared using procedures analogous to those forexample 204. MS (ESI) (M+H) 434.1

Example 416(3S,5S,6S)-5-[(hydroxyamino)carbonyl]-1-methyl-6-[(4-phenylpiperazin-1-yl)carbonyl]piperidin-3-ylazocane-1-carboxylate

This compound was prepared using procedures analogous to those forexample 204. MS (ESI) (M+H) 502.2

Example 417(2S,3S,5S)-5-(2-fluorophenoxy)-N-hydroxy-1-methyl-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 152. MS (ESI): (M+H) 457.2.

Example 418(2S,3S,5S)—N-hydroxy-1-methyl-5-[(6-methylpyridin-2-yl)oxy]-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 152. MS (ESI): (M+H) 454.2.

Example 419(2S,3S,5S)—N-hydroxy-1-methyl-2-[(4-phenylpiperazin-1-yl)carbonyl]-5-(pyridin-4-yloxy)piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 152. MS (ESI): (M+H) 440.1.

Example 420(2S,3S,5S)-5-(3-fluorophenoxy)-N-hydroxy-1-methyl-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 152. MS (ESI): (M+H) 457.2.

Example 421(2S,3S,5S)—N-hydroxy-1-methyl-2-[(4-phenylpiperazin-1-yl)carbonyl]-5-(pyridin-2-yloxy)piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 152. MS (ESI): (M+H) 440.2.

Example 422(2S,3S,5S)-5-(1,3-benzothiazol-2-yloxy)-N-hydroxy-1-methyl-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 152.

Example 423(2S,3S,5S)—N-hydroxy-1-methyl-5-(3-methylphenoxy)-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 152. MS (ESI): (M+H) 453.2.

Example 424(2S,3S,5S)—N-hydroxy-1-methyl-5-[(4-methylpyridin-2-yl)oxy]-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 152. MS (ESI): (M+H) 454.2.

Example 425(2S,3S,5S)-5-(3,4-difluorophenoxy)-N-hydroxy-1-methyl-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 152. MS (ESI): (M+H) 475.1.

Example 426(2S,3S,5S)-5-(2-chlorophenoxy)-N-hydroxy-1-methyl-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 152. MS (ESI): (M+H) 473.2.

Example 427(3S,5S,6S)-5-[(hydroxyamino)carbonyl]-1-methyl-6-[(4-phenylpiperazin-1-yl)carbonyl]piperidin-3-yl3,3-difluoropyrrolidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 204. MS (ESI) (M+H): 496.1.

Example 428methyl(2S,3S,5S)-3-[(hydroxyamino)carbonyl]-2-[(4-phenylpiperazin-1-yl)carbonyl]-5-(quinolin-6-yloxy)piperidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 126. ESI (MS): (M+H) 534.2.

Example 429(2S,3S,5S)—N-hydroxy-1-methyl-2-[(3-phenyl-2,5-dihydro-1H-pyrrol-1-yl)carbonyl]-5-(pyridin-3-yloxy)piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 152. MS (ESI): (M+H) 423.1.

Example 430(2S,3S,5S)—N-hydroxy-1-methyl-2-[(3-phenyl-2,5-dihydro-1H-pyrrol-1-yl)carbonyl]-5-(pyridin-4-yloxy)piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 152. MS (ESI): (M+H) 423.0.

Example 431(2S,3S,5S)-5-(3-fluorophenoxy)-N-hydroxy-1-methyl-2-[(3-phenyl-2,5-dihydro-1H-pyrrol-1-yl)carbonyl]piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 152. MS (ESI): (M+H) 440.1.

Example 432(2S,3S,5S)—N-hydroxy-1-methyl-5-phenoxy-2-[(3-phenyl-2,5-dihydro-1H-pyrrol-1-yl)carbonyl]piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 152. LCMS (ESI): (M+H) 422.1.

Example 433(2S,3S,5S)—N-hydroxy-1-methyl-2-[(3-phenyl-2,5-dihydro-1H-pyrrol-1-yl)carbonyl]-5-(pyridin-2-yloxy)piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 152. LCMS (ESI): (M+H) 423.1.

Example 434(2S,3S,5S)—N-hydroxy-1-methyl-5-[(4-methylpyridin-2-yl)oxy]-2-[(3-phenyl-2,5-dihydro-1H-pyrrol-1-yl)carbonyl]piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 152. MS (ESI): (M+H) 437.1.

Example 435(2S,3S,5S)—N-hydroxy-1-methyl-5-[(6-methylpyridin-2-yl)oxy]-2-[(3-phenyl-2,5-dihydro-1H-pyrrol-1-yl)carbonyl]piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 152. MS (ESI): (M+H) 437.1.

Example 436(2S,3S,5S)—N-hydroxy-1-methyl-2-[(4-phenylpiperazin-1-yl)carbonyl]-5-(pyridin-2-yloxy)piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 152. MS (ESI): (M+H) 440.2.

Example 437(2S,3S,5S)—N-hydroxy-1-methyl-2-[(4-phenylpiperazin-1-yl)carbonyl]-5-(pyridin-3-yloxy)piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 152. MS (ESI): (M+H) 440.1.

Example 438(2S,3S,5S)—N-hydroxy-1-methyl-5-[(2-methylquinolin-4-yl)oxy]-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 152. MS (ESI): (M+H) 504.2.

Example 439(2S,3S,5S)—N-hydroxy-1-methyl-5-[(2-methylquinolin-4-yl)oxy]-2-[(3-phenyl-2,5-dihydro-1H-pyrrol-1-yl)carbonyl]piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 152. MS (ESI): (M+H) 487.2.

Example 440(2S,3S,5S)—N-hydroxy-1-methyl-2-[(4-phenylpiperazin-1-yl)carbonyl]-5-(quinolin-4-yloxy)piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 152. MS (ESI): (M+H) 490.3.

Example 441(2S,3S,5S)—N-hydroxy-1-methyl-2-[(3-phenyl-2,5-dihydro-1H-pyrrol-1-yl)carbonyl]-5-(quinolin-6-yloxy)piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 152. MS (ESI): (M+H) 473.1.

Example 442(2S,3S,5S)—N-hydroxy-1-methyl-2-[(3-phenyl-2,5-dihydro-1H-pyrrol-1-yl)carbonyl]-5-(quinolin-4-yloxy)piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 152. MS (ESI): (M+H) 473.1.

Example 443(2S,3S,5S)—N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]-5-(pyridin-2-yloxy)piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 152. MS (ESI): (M+H) 426.1.

Example 444(2S,3S,5S)—N-hydroxy-1-methyl-5-[(4-methylpyridin-2-yl)oxy]-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 152. MS (ESI): (M+H) 454.2.

Example 445(2S,3S,5S)-5-[(5-chloropyridin-3-yl)oxy]-2-[4-(4-cyano-3,5-dimethylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl-N-hydroxypiperidine-3-carboxamidePart 1. tert-butyl4-[(trifluoromethyl)sulfonyl]oxy-3,6-dihydropyridine-1(2H)-carboxylate

To a solution of tert-butyl 4-oxo-1-piperidinecarboxylate (10.50 g,0.05270 mol) in tetrahydrofuran (200.0 mL) at −78 Celsius, undernitrogen, was added 1.00 M of lithium hexamethyldisilazide intetrahydrofuran (55.96 mL). After stirred at at −78 Celsius for 1 h, tothe resultant mixture was added solidN-phenylbis(trifluoromethanesulphonimide) (20.00 g, 0.05598 mol). Thereaction mixture was stirred at −78 Celsius for 2 h, then allowed towarm to rt gradually and stirred at rt overnight. After evaporation ofTHF under reduced pressure, the residue was diluted with ether. Themixture was washed with 1N HCl, 1N NaOH, and brine, successively. Theorganic layers were then dried and evaporated to dry. The residue wasapplied on silica gel column, eluting 0 to 20% ethyl acetate in hexane,to provide the enol triflate (14.60 g, 83.6%). MS (ESI): (M+2-Boc)232.0.

Part 2. tert-butyl4-(4-hydroxy-3,5-dimethylphenyl)-3,6-dihydropyridine-1(2H)-carboxylate

Nitrogen was bubbled through a mixture of tert-butyl4-[(trifluoromethyl)sulfonyl]oxy-3,6-dihydropyridine-1(2H)-carboxylate(5.80 g, 0.0175 mol),2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (4.82g, 0.0194 mol) and potassium carbonate (7.26 g, 0.0525 mol) inN,N-dimethylformamide (50.0 mL, 0.646 mol) for 10 min. To the reactionmixture was then added [1,F-Bis(diphenylphosphino)ferrocene]-dichloropalladium(II), complex withdichloromethane (1:1) (0.8 g, 0.001 mol). The resultant mixture washeated at at 80 Celsius overnight. After quenched with water, themixture was neutralized with 1N HCl, extracted with ethyl acetate. Thecombined organic layers were washed with water, brine, dried andevaporated to dry. The residue was applied on column, eluting with 0 to50% EtOAc in hexane, to yield the desired product (4.36 g, 82.09%). MS(ESI): (M-Boc+2) 204.0.

Part 3. tert-butyl4-(3,5-dimethyl-4-[(trifluoromethyl)sulfonyl]oxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate

To a solution of tert-butyl4-(4-hydroxy-3,5-dimethylphenyl)-3,6-dihydropyridine-1(2H)-carboxylate(2.30 g, 0.00758 mol) in methylene chloride (50.0 mL, 0.780 mol) at −78Celsius was added triethylamine (3.17 mL, 0.0227 mol), followed bytrifluoromethane-sulfonic anhydride (1.40 mL, 0.00834 mol). The reactionmixture was allowed to slowly warm to rt over a period of 1.5 h. Thereaction was quenched with satd. aqueous ammonium chloride and extractedwith ethyl acetate. The combined organic layers were washed with brine,then dried (sodium sulfate) and were concentrated. The resulting residuewas purified by flash chromatography (eluting with 0 to 10%EtOAc/Hexane) to provide the triflate as a yellow oil (3.10 g, 93.91%).MS (ESI): (M-Bu+1): 380.0.

Part 4. tert-butyl4-(4-cyano-3,5-dimethylphenyl)-3,6-dihydropyridine-1(2H)-carboxylate

A mixture of tert-butyl4-(3,5-dimethyl-4-[(trifluoromethyl)sulfonyl]oxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate(2.80 g, 0.00643 mol) and zinc cyanide (1.51 g, 0.0128 mol) inN,N-dimethylformamide (15.0 mL, 0.194 mol) was degassed with nitrogenfor 15 min. To the mixture was addedtetrakis(triphenylphosphine)palladium(O) (0.74 g, 0.00064 mol). Thereaction mixture was heated at 100 Celsius for 4 h. The mixture wasdiluted with ether, washed with aq. sodium bicarbonate, brine, driedover magnesium sulfate and evaporated in vacuo. The residue was purifiedon silica gel, eluting with 0 to 10% EtOAc in hexane, to generate Thetitled compound (1.08 g, 53.66%). LCMS (M+H) 313.1 Part 5. 1-tert-butyl3-methyl(2S,3S,5R)-2-[4-(4-cyano-3,5-dimethylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl-5-hydroxypiperidine-1,3-dicarboxylate(1) tert-butyl4-(4-cyano-3,5-dimethylphenyl)-3,6-dihydropyridine-1(2H)-carboxylate(0.88 g, 0.0028 mol) was treated with 5 mL of TFA at rt for 1 h. Afterevaporated to dry, the resultant TFA salt was used directly in nextstep.

(2) To a mixture of(2S,3S,5R)-5-hydroxy-3-(methoxycarbonyl)piperidine-2-carboxylic acid(0.477 g, 0.00235 mol) and the TFA salt made above inN,N-dimethylformamide (2.38 mL, 0.0308 mol) was addedbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(1.24 g, 0.00282 mol), followed by N,N-diisopropylethylamine (0.981 mL,0.00563 mol) at 0 Celsius. The resultant mixture was stirred at rt for 3h. After quenched with aq. sodium bicarbonate, the mixture was extractedwith methylene chloride. The combined organic layers were dried andevaporated under reduced pressure.

(3) The residue was then diluted with methylene chloride (4.77 mL,0.0744 mol) and treated with N,N-diisopropylethylamine (0.818 mL,0.00469 mol) followed by di-tert-butyldicarbonate (1.02 g, 0.00469 mol)at rt overnight. The reaction was diluted with aq. sodium bicarbonate,extracted with ethyl acetate. The combined organic layers were driedwashed with brine, dried and evaporated to dry in vacuo. The residue wasapplied on silica gel, eluting with 0 to 100% EtOAc in hexane, toprovide the desired product (790 mg, 67.64%). MS (ESI): (M-Boc+2H)398.1.

Part 6. 1-tert-butyl3-methyl(2S,3S,5S)-5-[(5-chloropyridin-3-yl)oxy]-2-[4-(4-cyano-3,5-dimethylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonylpiperidine-1,3-dicarboxylate

To a solution of 1-tert-butyl3-methyl(2S,3S,5R)-2-[4-(4-cyano-3,5-dimethylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl-5-hydroxypiperidine-1,3-dicarboxylate(100 mg, 0.0002 mol) in tetrahydrofuran (0.912 mL, 0.0112 mol) was added5-chloropyridin-3-ol (35.0 mg, 0.000270 mol), triphenylphosphine (70.8mg, 0.000270 mol), followed by diisopropyl azodicarboxylate (0.0532 mL,0.000270 mol). The mixture was heated at 70 Celsius overnight. Afterconcentrated to dry, the mixture was purified on silica gel, elutionwith 0 to 40% EtOAc in hexane, to yield the desired product (45 mg,32.84%). MS (ESI) (M+H) 609.1.

Part 7

1-tert-butyl3-methyl(2S,3S,5S)-5-[(5-chloropyridin-3-yl)oxy]-2-[4-(4-cyano-3,5-dimethylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonylpiperidine-1,3-dicarboxylatewas treated with hydroxylamine solution in methanol, using proceduresanalogous to those for example 152, to provide the titled product. ESIMS: (M+H) 510.1.

Example 446(2S,3S,5S)-2-[4-(4-cyano-3,5-dimethylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl-N-hydroxy-5-[(6-methylpyridin-2-yl)oxy]piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 445. ESI MS: (M+H) 490.1.

Example 447(2S,3S,5S)-2-[4-(4-cyano-3,5-dimethylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl-N-hydroxy-5-[(4-methylpyridin-2-yl)oxy]piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 445. ESI MS: (M+H) 490.2.

Example 448(2S,3S,5S)-2-[4-(4-cyano-3,5-dimethylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl-N-hydroxy-5-(pyridin-2-yloxy)piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 445. ESI MS: (M+H) 476.2.

Example 449(2S,3S,5S)-2-[4-(4-cyano-3,5-dimethylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl-N-hydroxy-5-phenoxypiperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 445. ESI MS: (M+H) 475.2.

Example 450(2S,3S,5S)—N-hydroxy-2-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]-5-(pyridin-2-yloxy)piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 152. ESI MS: (M+H) 423.1.

Example 451(2S,3S,5S)-2-[4-(4-cyano-3,5-dimethylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl-N-hydroxy-5-[(3-methyl-1H-pyrazol-5-yl)oxy]piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 445.

Example 452(2S,3S,5S)—N-hydroxy-5-[(5-methylisoxazol-3-yl)oxy]-2-[(3R)-3-phenylpyrrolidin-1-yl]carbonylpiperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 152. ESI MS: (M+H) 415.1.

Example 453(2S,3S,5S)—N-hydroxy-5-[(3-methyl-1H-pyrazol-5-yl)oxy]-2-[(3R)-3-phenylpyrrolidin-1-yl]carbonylpiperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 152. ESI MS: (M+H) 414.1.

Example 454(2S,3S,5S)-5-[(5-chloropyridin-3-yl)oxy]-N-hydroxy-2-[(3R)-3-phenylpyrrolidin-1-yl]carbonylpiperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 152. ESI MS: (M+H) 445.1.

Example 455(2S,3S,5S)—N-hydroxy-5-[(4-methylpyridin-2-yl)oxy]-2-[(3R)-3-phenylpyrrolidin-1-yl]carbonylpiperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 152. ESI MS: (M+H) 425.0.

Example 456(2S,3S,5S)—N-hydroxy-2-[(3R)-3-phenylpyrrolidin-1-yl]carbonyl-5-(pyridin-2-yloxy)piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 152. ESI MS: (M+H) 411.1.

Example 457(2S,3S,5S)-2-[4-(4-cyano-3,5-dimethylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl-5-(3,4-difluorophenoxy)-N-hydroxypiperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 152. ESI MS: (M+H) 511.1.

Example 458(2S,3S,5S)-2-[4-(4-cyano-3,5-dimethylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl-N-hydroxy-5-[(5-methylisoxazol-3-yl)oxy]piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 152. ESI MS: (M+H) 480.1.

Example 459(2S,3S,5S)-2-[4-(4-cyano-3,5-dimethylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl-N-hydroxy-5-[(2-methylquinolin-4-yl)oxy]piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 152. ESI MS: (M+H) 540.1.

Example 460(2S,3S,5S)—N-hydroxy-5-[(2-methylquinolin-4-yl)oxy]-2-[(3R)-3-phenylpyrrolidin-1-yl]carbonylpiperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 296. ESI MS: (M+H) 475.1.

Example 461(2S,3S)-2-[4-(4-cyano-3,5-dimethylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl-5,5-difluoro-N-hydroxy-1-methylpiperidine-3-carboxamidePart 1. 1,2-dibenzyl3-tert-butyl(2S,3S)-5,5-difluoropiperidine-1,2,3-tricarboxylate

A solution of 1,2-dibenzyl3-tert-butyl(2S,3S)-5-oxopiperidine-1,2,3-tricarboxylate (1.87 g,0.00400 mol) in methylene chloride (3.00 mL, 0.0468 mol), contained in ateflon bottle equipped with a nitrogen inlet tube and stirring bar, wastreated with2-methoxy-N-(2-methoxyethyl)-N-(trifluoro-<lambda>(4)-sulfanyl)ethanamine(1.25 mL, 0.00680 mol) at rt. Ethanol (0.047 mL, 0.00080 mol) was added,and the mixture was stirred at rt overnight. On completion, the solutionwas poured into saturated sodium bicarbonate, extracted with methylenechloride, dried and evaporated in vacuo. Flash chromatography on silicagel in 0 to 10% EtOAc/hexane afforded the pure product (370 mg, 18.9%).MS (ESI): (M+Na) 512.1. The product was contaminated with small amount(inseperable) of corresponding vinyl floride (M+Na) 493.1.

Part 2.(2S,3S)-3-(tert-butoxycarbonyl)-5,5-difluoropiperidine-2-carboxylic acid

A solution of 1,2-dibenzyl3-tert-butyl(2S,3S)-5,5-difluoropiperidine-1,2,3-tricarboxylate (0.370g, 0.000756 mol) in EtOH (7.0 mL) was hydrogenated in the presence of10% Pd/C, under a ballon pressure of hydrogen, for 2 h. After filteredoff the catalyst, the filtration was evaporated to dry. The residue wasused directly in next step (190 mg, 94.77%). LC MS (M-Bu+1) 210.0.

Part 3.tert-butyl(2S,3S)-2-[4-(4-cyano-3,5-dimethylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl-5,5-difluoropiperidine-3-carboxylate

To a mixture of(2S,3S)-3-(tert-butoxycarbonyl)-5,5-difluoropiperidine-2-carboxylic acid(48 mg, 0.00018 mol) and2,6-dimethyl-4-(1,2,3,6-tetrahydropyridin-4-yl)benzonitrilehydrochloride (84.7 mg, 0.000217 mol) TFA salt in N,N-dimethylformamide(0.406 mL, 0.00524 mol) was addedbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(96.0 mg, 0.000217 mol), followed by N,N-diisopropylethylamine (0.0756mL, 0.000434 mol). The mixture was stirred at rt overnight, thenquenched with aq. sodium bicarbonate. The mixture was extracted withEtOAc. The combined organic layers were washed with water, brine, dried,and evaporated to dry. The residue was used directly in next stepwithout further purification. LCMS (M+H) 460.2.

Part 4tert-butyl(2S,3S)-2-[4-(4-cyano-3,5-dimethylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl-5,5-difluoro-1-methylpiperidine-3-carboxylate

The crude reaction mixture from 3256-82 was diluted with acetonitrile(0.64 mL, 0.012 mol) and tetrahydrofuran (0.64 mL, 0.0078 mol). To themixture was added 12.32 M of formaldehyde in water (0.035 mL) followedby sodium triacetoxyborohydride (92 mg, 0.00044 mol). After stirred atrt overnight, the mixture was evaporated to dry, diluted with aq. sodiumbicarbonate, and extracted with EtOAc. The combined organic layers werewashed with water, brine and dried. After evaporated to dry, the residuewas used directly in next step. LCMS (M+H) 474.2.

Part 5.(2S,3S)-2-[4-(4-cyano-3,5-dimethylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl-5,5-difluoro-N-hydroxy-1-methylpiperidine-3-carboxamide

(1)tert-Butyl(2S,3S)-5,5-difluoro-2-[(4-[(2-methylquinolin-4-yl)methoxy]phenylamino)-carbonyl]piperidine-3-carboxylatewas treated with 0.5 mL of TFA at rt for 30 min. After evaporation ofthe TFA, the residue was exposured on high vaccum and then used directlyin next step.

(2) To a mixture of the crude TFA salt made above inN,N-dimethylformamide (0.20 mL, 0.0025 mol) was added N-hydroxyaminehydrochloride (7.44 mg, 0.000107 mol), andbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(47.4 mg, 0.000107 mol). After stirred for 10 min, to the mixture wasadded N,N-diisopropylethylamine (0.0373 mL, 0.000214 mol). The resultingmixture was stirred at rt overnight. The crude mixture was applieddirectly on RP-HPLC to generate the desired product as a TFA salt. LC MS(M+H) 433.1.

Example 462(2S,3S)-2-[4-(4-cyano-3,5-dimethylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl-5,5-difluoro-N-hydroxypiperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 461. LC MS (M+H) 419.1.

Example 463(2S,3S)-5,5-difluoro-N-hydroxy-2-[4-(3-isopropylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl-1-methylpiperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 461. LC MS (M+H) 422.2.

Example 464(2S,3S)-5,5-difluoro-N-hydroxy-2-[4-(3-isopropylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonylpiperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 461. LC MS (M+H) 408.15.

Example 465(2S,3S)-5,5-difluoro-N(3)-hydroxy-1-methyl-N(2)-4-[(2-methylquinolin-4-yl)methoxy]phenylpiperidine-2,3-dicarboxamide

This compound was prepared using procedures analogous to those forexample 461. LC MS (M+H) 485.1.

Example 466(2S,3S)-5,5-difluoro-N(3)-hydroxy-N(2)-4-[(2-methylquinolin-4-yl)methoxy]phenylpiperidine-2,3-dicarboxamide

This compound was prepared using procedures analogous to those forexample 461. LC MS (M+H) 471.1.

Example 467(3S,5S,6S)-5-[(hydroxyamino)carbonyl]-6-[(4-[(2-methylquinolin-4-yl)methoxy]phenylamino)carbonyl]piperidin-3-ylazepane-1-carboxylate

This compound was prepared using procedures analogous to those forexample 204. LC MS (M+H) 576.2.

Example 468(2S,3S,5R)-5-fluoro-N(3)-hydroxy-N(2)-4-[(2-methylquinolin-4-yl)methoxy]phenylpiperidine-2,3-dicarboxamideStep 1

2-benzyl3-methyl(2S,3S,5S)-1-benzyl-5-hydroxypiperidine-2,3-dicarboxylate (1.89g, 0.00493 mol) was dissolved in methylene chloride (2.7 mL, 0.042 mol),cooled to −78 Celsius, and then treated with diethylaminosulfurtrifluoride (0.650 mL, 0.00492 mol) (DAST). The resulting reactionmixture was warmed to rt and stirred at rt for 18 h. The reactionmixture was poured into ice-water containing NaHCO₃, extracted withCH₂Cl₂ (3×). The organic layers were dried over Na₂SO₄, concentrated andpurified on silica gel (eluting with 0-5% MeOH in CH₂Cl₂). Yield: 1.73g, 91.24%. LCMS (M+H) 386.1

Step 2

To a soln. of the product made above (1.73 g, 0.00449 mol) in methanol(20 mL, 0.5 mol) was added 0.34 g of Pd/C (10% wt. on activated carbon,wet), then hydrogenated on par shaker at 43 psi for 3 h. Afterfiltration, the filtrate was concentrated under reduced pressure anddried under high vacuum to give(2S,3S,5R)-5-fluoro-3-(methoxycarbonyl)piperidine-2-carboxylic acid as awhite solid. LC-MS (M+H) 206.1

Step 3

To a mixture of(2S,3S,5R)-5-fluoro-3-(methoxycarbonyl)piperidine-2-carboxylic acid(75.0 mg, 0.000366 mol) and 4-[(2-methylquinolin-4-yl)methoxy]anilinedihydrochloride (148 mg, 0.000439 mol) in N,N-dimethylformamide (0.56mL, 0.0073 mol) was addedbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(194 mg, 0.000439 mol) followed by N,N-diisopropylethylamine (0.229 mL,0.00132 mol). After stirred at rt for 2 h, the reaction was quenchedwith aq. sodium bicarbonate, extracted with EtOAc. The combined organiclayers were washed with brine, dried and evaporated to dry under reducedpressure. The residue was used directly in next step. LCMS (M+H) 452.1.

Step 4

methyl(2S,3S,5R)-5-fluoro-2-[(4-[(2-methylquinolin-4-yl)methoxy]-phenylamino)carbonyl]piperidine-3-carboxylate(80.0 mg, 0.000177 mol) was treated with 1.640 M of N-hydroxyamine inmethanol (2.161 mL) (made from hydroxylamine HCl salt and sodiummethoxide) at rt for 2 h. After acidified with 1:1 TFA/water, themixture was applied directly on RP-HPLC to give the product as TFA salt.LC MS (M+H) 453.0.

Example 469(3S,5S,6S)-5-[(hydroxyamino)carbonyl]-1-methyl-6-[(4-[(2-methylquinolin-4-yl)methoxy]phenylamino)carbonyl]piperidin-3-ylazepane-1-carboxylate

This compound was prepared using procedures analogous to those forexample 204. LCMS (M+H)=590.2.

Example 470(3S,5S,6S)-6-[4-(4-cyano-3,5-dimethylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl-5-[(hydroxyamino)carbonyl]piperidin-3-ylazepane-1-carboxylate

This compound was prepared using procedures analogous to those forexample 204. LCMS (M+H) 524.2.

Example 471(2S,3S,5R)-5-fluoro-N-hydroxy-1-methyl-2-[(3R)-3-phenylpyrrolidin-1-yl]carbonylpiperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 468. LCMS (M+H) 350.1.

Example 472(2S,3S,5R)-5-fluoro-N-hydroxy-2-[(3R)-3-phenylpyrrolidin-1-yl]carbonylpiperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 468. LCMS (M+H) 336.1.

Example 473(2S,3S,5S)—N-hydroxy-5-phenoxy-2-[(3-phenyl-2,5-dihydro-1H-pyrrol-1-yl)carbonyl]piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 152. LCMS (M+H) 408.2.

Example 474(2S,3S,5S)—N-hydroxy-2-[(3-phenyl-2,5-dihydro-1H-pyrrol-1-yl)carbonyl]-5-(pyridin-2-yloxy)piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 152. LCMS (M+H) 409.2, (M+Na) 431.2

Example 475(2S,3S,5S)—N-hydroxy-2-[(3-phenyl-2,5-dihydro-1H-pyrrol-1-yl)carbonyl]-5-(pyridin-4-yloxy)piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 152. LCMS (M+H) 409.2, (M+Na) 431.2

Example 476(2S,3S,5S)—N-hydroxy-2-[(3-phenyl-2,5-dihydro-1H-pyrrol-1-yl)carbonyl]-5-(pyridin-3-yloxy)piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 152. LCMS (M+H) 409.2, (M+Na) 431.2

Example 477(2S,3S,5S)—N-hydroxy-5-[(6-methylpyridin-2-yl)oxy]-2-[(3-phenyl-2,5-dihydro-1H-pyrrol-1-yl)carbonyl]piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 152. LCMS (M+H) 423.2

Example 478(2S,3S,5S)—N-hydroxy-5-[(4-methylpyridin-2-yl)oxy]-2-[(3-phenyl-2,5-dihydro-1H-pyrrol-1-yl)carbonyl]piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 152. LCMS (M+H) 423.2

Example 479(2S,3S,5S)-5-(3-fluorophenoxy)-N-hydroxy-2-[(3-phenyl-2,5-dihydro-1H-pyrrol-1-yl)carbonyl]piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 152. LCMS (M+H) 426.2

Example 480(2S,3S,5S)—N-hydroxy-2-[(3-phenyl-2,5-dihydro-1H-pyrrol-1-yl)carbonyl]-5-(quinolin-6-yloxy)piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 152. LCMS (M+H) 459.2

Example 481(2S,3S,5S)—N-hydroxy-2-[(3-phenyl-2,5-dihydro-1H-pyrrol-1-yl)carbonyl]-5-(quinolin-7-yloxy)piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 152. LCMS (M+H) 459.2

Example 482(2S,3S,5S)—N-hydroxy-2-[(3-phenyl-2,5-dihydro-1H-pyrrol-1-yl)carbonyl]-5-(quinolin-4-yloxy)piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 152. LCMS (M+H) 459.2

Example 483(2S,3S,5S)—N-hydroxy-5-[(2-methylquinolin-4-yl)oxy]-2-[(3-phenyl-2,5-dihydro-1H-pyrrol-1-yl)carbonyl]piperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 152. LCMS (M+H) 473.2.

Example 484(2S,3S,5R)-2-[4-(4-cyano-3,5-dimethylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl-5-fluoro-N-hydroxypiperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 468. (M+H) 401.2.

Example 485(2S,3S,5R)-5-fluoro-N-hydroxy-2-[4-(3-isopropylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonylpiperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 468. (M+H) 390.2.

Example 486(2S,3S,5R)-2-[4-(4-cyano-3,5-dimethylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl-5-fluoro-N-hydroxy-1-methylpiperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 468. (M+H) 415.2.

Example 487(2S,3S,5R)-5-fluoro-N-hydroxy-2-[4-(3-isopropylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl-1-methylpiperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 468. LCMS (M+H) 404.2 (base)

Example 4881S,2S,5E)-5-benzylidene-2-[4-(4-cyano-2-methylphenyl)piperazin-1-yl]carbonyl-N-hydroxycyclohexanecarboxamidetrifluoroacetate (salt

This compound was prepared using procedures analogous to those forexample 241. The crude products were purified by reverse phase HPLC with5-95% MeCN/H₂O (with 0.05% TFA, pH=2.5) to give the trans product [Peak1, 3.6 mg, 14% in yield, (M+H)=459.2] as a colorless solid as well asthe cis product as a colorless solid [peak 2, 1.9 mg, 7% in yield,(M+H)=459.2].

Example 4891S,2S,5E)-2-[4-(4-cyano-2-methylphenyl)piperazin-1-yl]carbonyl-5-(cyclopropylmethylene)-N-hydroxycyclohexanecarboxamidetrifluoroacetate (salt

This compound was prepared using procedures analogous to those forexample 241. The crude material was purified by reverse phase HPLC with5-95% MeCN/H₂O (with 0.05% TFA) to give the trans product [peak 1, 12.0mg, 20% in yield, (M+H)=423.2] as a colorless solid as well as the cisproduct as a colorless solid [peak 2, 6.4 mg, 11% in yield,(M+H)=423.2].

Example 490(1S,2S,5E)-5-benzylidene-N-hydroxy-2-[(3R)-3-phenylpyrrolidin-1-yl]carbonylcyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 241. The crude material was purified by reverse phase HPLC with5-95% MeCN/H₂O (with 0.05% TFA, pH=2) to give the trans product as acolorless solid [peak 1, 20.5 mg, 48% in yield, (M+H)=405.1] as well ascis product as a colorless solid [peak 2, 9.4 mg, 22% in yield,(M+H)=405.2].

Example 491(1S,2S,5S)—N,5-dihydroxy-5-isobutyl-2-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 244. LCMS (M+Na)=423.2.

Example 492(1S,2S,5S)-5-butyl-N,5-dihydroxy-2-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]cyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 243. LCMS (M+H)=401.2.

Example 4931R,3S,4S)-3-[(hydroxyamino)carbonyl]-1-methyl-4-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexylazetidine-1-carboxylate trifluoroacetate (salt

This compound was prepared using procedures analogous to those forexample 204. LCMS (M+H)=445.2.

Example 4941S,3S,4S)-3-[(hydroxyamino)carbonyl]-1-methyl-4-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexylpyrrolidine-1-carboxylate trifluoroacetate (salt

This compound was prepared using procedures analogous to those forexample 204. LCMS (M+Na)=481.2.

Example 4951S,2S,5S)—N,5-dihydroxy-5-isobutyl-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxamidetrifluoroacetate (salt

This compound was prepared using procedures analogous to those forexample 244. LCMS (M+H)=404.0.

Example 4961S,2S,5R)-5-(cyclopropylmethyl)-N,5-dihydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxamidetrifluoroacetate (salt

This compound was prepared using procedures analogous to those forexample 243. LC MS (M+H)=402.1.

Example 4971S,2S,5R)-5-butyl-N,5-dihydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxamidetrifluoroacetate (salt

This compound was prepared using procedures analogous to those forexample 244. The crude material was purified by reverse phase HPLC with5-95% MeCN/H₂O (with 0.05% TFA) to give the ax-OH product [peak2, 9.1mg, 5% in yield for two steps, (M+H)=404.2] as a colorless solid as wellas the eq-OH product [peak1, 1.5 mg, 1% in yield for two steps,(M+H)=404.2] as a colorless solid.

Example 4981R,3S,4S)-3-[(hydroxyamino)carbonyl]-1-methyl-4-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexylpyrrolidine-1-carboxylate trifluoroacetate (salt

This compound was prepared using procedures analogous to those forexample 204. LCMS (M+H)=459.2.

Example 499(1S,2S,5E)-5-(cyclopropylmethylene)-N-hydroxy-2-[(3R)-3-phenylpyrrolidin-1-yl]carbonylcyclohexanecarboxamide

This compound was prepared using procedures analogous to those forexample 241. The crude material was purified by reverse phase HPLC with5-95% MeCN/H₂O (with 0.05% TFA) to give the peak1 [9.8 mg, 33% in yield,(M+H)=369.2] as a colorless solid as well as the peak2 [7.6 mg, 25% inyield, (M+H)=369.2] as a colorless solid.

Example 5001S,2S,5R)-5-ethyl-N,5-dihydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxamidetrifluoroacetate (salt

This compound was prepared using procedures analogous to those forexample 244. The crude material was purified by reverse phase HPLC with5-95% MeCN/H₂O (with 0.05% TFA) to give the ax-OH product [peak2, 39.1mg, 22% in yield for two steps, (M+H)=376.2] as a colorless solid aswell as the eq-OH product [peak1, 25.0 mg, 14% in yield for two steps,(M+H)=376.2] as a colorless solid.

Example 501(3R,4S)-1-[(E)-(cyanoimino)(cyclopropylamino)methyl]-4-[4-(4-cyano-2-methylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl-N-hydroxypiperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 220. LCMS (M+H)=476.2.

Example 502(3R,4S)-1-[(E)-(cyanoimino)(dimethylamino)methyl]-4-[4-(4-cyano-2-methylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl-N-hydroxypiperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 220. LCMS (M+H)=464.2.

Example 503(3R,4S)-1-[(E)-(cyanoimino)(piperidin-1-yl)methyl]-4-[4-(4-cyano-2-methylphenyl)piperazin-1-yl]carbonyl-N-hydroxypiperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 220. LCMS (M+H) 507.2.

Example 504(3R,4S)-1-[(E)-azetidin-1-yl(cyanoimino)methyl]-4-[4-(4-cyano-2-methylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl-N-hydroxypiperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 220. LCMS (M+H) 476.1.

Example 505(3R,4S)-1-[(E)-azetidin-1-yl(cyanoimino)methyl]-4-[4-(4-cyano-2-methylphenyl)piperidin-1-yl]carbonyl-N-hydroxypiperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 220. LCMS (M+H) 478.1.

Example 506(3R,4S)-1-[(E)-(cyanoimino)(pyrrolidin-1-yl)methyl]-4-[4-(4-cyano-2-methylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl-N-hydroxypiperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 220. LCMS (M+H)=490.2

Example 507(3R,4S)-1-[(E)-(cyanoimino)(piperidin-1-yl)methyl]-4-[4-(4-cyano-2-methylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl-N-hydroxypiperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 220. LCMS (M+H) 504.2.

Example 508(3R,4S)-1-[(E)-(cyanoimino)(piperidin-1-yl)methyl]-4-[4-(4-cyano-2-methylphenyl)piperidin-1-yl]carbonyl-N-hydroxypiperidine-3-carboxamide

This compound was prepared using procedures analogous to those forexample 220. LCMS (M+H)=506.2.

The structural aspects of the novel compounds exemplified above aresummarized in Table 1 through Table 7.

TABLE 1

Ex. R QY MS 42 tetrahydrofuran-(3S)-yl oxo- 4-(3-isopropyl-phenyl)-488.2 carbonyl piperidinyl 43 tetrahydrofuran-(3R)-yl oxo-4-(3-isopropyl-phenyl)- 488.2 carbonyl piperidinyl 44tetrahydro-2H-pyran-4-yl 4-(3-isopropyl-phenyl)- 502.2 oxo-carbonylpiperidinyl 45 tetrahydrofuran-(3R)-yl oxo- 4-phenyl-piperazinyl 447.2carbonyl 46 tetrahydrofuran-(3S)-yl oxo- 4-phenyl-piperazine 447.2carbonyl 47 tetrahydro-2H-pyran-4-yl 4-phenyl-piperazine 461.2oxo-carbonyl 71 tetrahydrofuran-(3S)-yl oxo- 4-(4-tert-Butyl-phenyl)-503.3 carbonyl piperazinyl

TABLE 2

Ex. R R¹/R² QY MS  1 H (R)-[(3R)-hydroxy- 4-(4-Cyano-2-methyl- 454.1pyrrolin-1-yl] phenyl)-3,6-dihydro-2H- pyridinyl  2 H (RS)-[(2-4-(4-Cyano-2-methyl- 497   dimethylamino- phenyl)-3,6-dihydro-2H-ethylcarbamoyl)- pyridinyl methyl]  3 H (R)-{[2-(3R)-hydroxy-4-(4-Cyano-2-methyl- 496.2 pyrrolidin-1-yl]-2- phenyl)-3,6-dihydro-2H-oxo-ethyl} pyridinyl  3 H (S)-{[2-(3R)-hydroxy- 4-(4-Cyano-2-methyl-496.2 pyrrolidin-1-yl]-2- phenyl)-3,6-dihydro-2H- oxo-ethyl} pyridinyl 4 H (S)-(2-morpholin-4- 4-(4-Cyano-2-methyl- 496.2 yl-2-oxo-ethyl)phenyl)-3,6-dihydro-2H- pyridinyl  4 H (R)-(2-morpholin-4-4-(4-Cyano-2-methyl- 496.2 yl-2-oxo-ethyl) phenyl)-3,6-dihydro-2H-pyridinyl  5 H (R)-[2-(4-hydroxy- 4-(4-Cyano-2-methyl- 510.3piperidin-1-yl)-2-oxo- phenyl)-3,6-dihydro-2H- ethyl] pyridinyl  5 H(S)-[2-(4-hydroxy- 4-(4-Cyano-2-methyl- 510.3 piperidin-1-yl)-2-oxo-phenyl)-3,6-dihydro-2H- ethyl] pyridinyl  6 H (R)-[(2-methoxy-4-(4-Cyano-2-methyl- 473.2 acetyl)-methyl-amino] phenyl)-piperazin-1yl 6 H (S)-[(2-methoxy- 4-(4-Cyano-2-methyl- 473.2 acetyl)-methyl-amino]phenyl)-piperazin-1yl  7 H (S)-[(2-methoxy- 4-(4-Cyano-2-methyl- 484.2ethylcarbamoyl)- phenyl)-3,6-dihydro-2H- methyl] pyridinyl  7 H(R)-[(2-methoxy- 4-(4-Cyano-2-methyl- 484.2 ethylcarbamoyl)-phenyl)-3,6-dihydro-2H- methyl] pyridinyl  8 H (S)-[(tetrahydro-furan-4-(4-Cyano-2-methyl- 496.2 (3R)-ylcarbamoyl)- phenyl)-3,6-dihydro-2H-methyl] pyridinyl  8 H (R)-[(tetrahydro- 4-(4-Cyano-2-methyl- 496.2furan-(3R)- phenyl)-3,6-dihydro-2H- ylcarbamoyl)-methyl] pyridinyl  9 H(R)-[methoxy- (3R)-phenyl-pyrrolidinyl 392.2 carbonyloxy]  9 H(S-[methoxy- (3R)-phenyl-pyrrolidinyl 392.2 carbonyloxy]  10 H(RS)-Hydroxy (3R)-phenyl-pyrrolidinyl 334.2  11 H (RS)-[Methylamino-(3R)-phenyl-pyrrolidinyl 391.2 carbonyloxy]  48 H (RS)-{2-[(5-Cbz-(3RS)-phenyl-pyrrolidinyl 594   aminopentyl)amino]- 2-oxoethyl}  49 H(RS)-{24(5- (3RS)-phenyl-pyrrolidinyl 460   aminopentyl)amino]-2-oxoethyl}  54 H (R)-Hydroxy 4-(3-isopropyl-phenyl)- 388.33,6-dihydro-2H-pyridinyl  54 H (S)-Hydroxy 4-(3-isopropyl-phenyl)- 388.33,6-dihydro-2H-pyridinyl  55 H (R)-Hydroxy 4-phenyl-piperazinyl 349.3 55 H (S)-Hydroxy 4-phenyl-piperazinyl 349.3  56 H (R)-(2-Morpholin-4-4-phenyl-piperazinyl 460.3 yl-2-oxo-ethyl)  56 H (S)-(2-Morpholin-4-4-phenyl-piperazinyl 460.3 yl-2-oxo-ethyl)  57 H (R)-Hydroxy4-(3-isopropyl-phenyl)- 390.2 piperidinyl  57 H (S)-Hydroxy4-(3-isopropyl-phenyl)- 390.2 piperidinyl  58 H (S)-(2-Morpholin-4-4-(3-isopropyl-phenyl)- 501.3 yl-2-oxo-ethyl) piperidinyl  58 H(S)-(2-Morpholin-4- 4-(3-isopropyl-phenyl)- 501.3 yl-2-oxo-ethyl)piperidinyl  70 Me (R)-[(Pyrrolidin-1-yl)- (3R)-phenyl-pyrrolidinyl445.2 carbonyloxy]  70 Me (S)-[(Pyrrolidin-1-yl)-(3R)-phenyl-pyrrolidinyl 445.2 carbonyloxy]  81 H [(Pyrrolidin-1-yl)-4-phenyl-3,6-dihydro-2H- 443.2 carbonyloxy] pyridinyl  82 H[(Pyrrolidin-1-yl)- 4-phenyl-piperidinyl 445.5 carbonyloxy]  84 H(2-Oxo-2- (3R)-phenyl-pyrrolidinyl 443.3 piperidin-1-yl-ethyl)  85 H(R)-(2-Oxo-2- (3R)-phenyl-pyrrolidinyl 429.3 pyrrolidin-1-yl-ethyl)  85H (S)-(2-Oxo-2- (3R)-phenyl-pyrrolidinyl 429.3 pyrrolidin-1-yl-ethyl) 86 H (RS)-(2-Oxo-2- 4-phenyl-piperazinyl 444.0 pyrrolidin-1-yl-ethyl) 87 H (RS)-(2-Oxo-2- 4-phenyl-piperazinyl 458.2 piperidin-1-yl-ethyl) 88 Me (RS)-(2-Oxo-2- 4-phenyl-piperazinyl 472.1 piperidin-1-yl-ethyl) 89 Me (RS)-(2-Oxo-2- 4-phenyl-piperazinyl 458.2 pyrrolidin-1-yl-ethyl) 90 Me (RS)-(2-Oxo-2- (3R)-phenyl-pyrrolidinyl 457.1piperidin-1-yl-ethyl)  91 Me (RS)-(2-Oxo-2- (3R)-phenyl-pyrrolidinyl443.0 pyrrolidin-1-yl-ethyl)  93 H (RS)-(Isobutyryl-(3R)-phenyl-pyrrolidinyl 417.2 methyl-amino)  94 H (RS)-(Isobutyryl-3-phenyl-2,5-dihydro- 415.2 methyl-amino) pyrrolyl  95 H(RS)-(Isobutyryl- 4-phenyl-3,6-dihydro-2H- 429.2 methyl-amino) pyridinyl 96 H (RS)-(Isobutyryl- 4-phenyl-piperidinyl 431.3 methyl-amino)  97 H(RS)-(Isobutyryl- 4-phenyl-piperazinyl 432.3 methyl-amino) 103 H(RS)-[(Pyrrolidin-1- (3R)-phenyl-pyrrolidinyl 431.2 yl)-carbonyloxy] 104H (RS)-[(Pyrrolidin-1- 4-phenyl-piperazinyl 446.2 yl)-carbonyloxy] 105 H(RS)-[(Pyrrolidin-1- 3-phenyl-2,5-dihydro- 429.2 yl)-carbonyloxy]pyrrolyl 106 CO₂Me (RS)-[(Pyrrolidin-1- 3-phenyl-2,5-dihydro- 487.2yl)-carbonyloxy] pyrrolyl 107 CO₂Me (RS)-[(Pyrrolidin-1-(3R)-phenyl-pyrrolidinyl 489.2 yl)-carbonyloxy] 108 CO₂Me(RS)-[(Pyrrolidin-1- 4-phenyl-piperidinyl 503.3 yl)-carbonyloxy] 109CO₂Me (RS)-[(Pyrrolidin-1- 4-phenyl-3,6-dihydro-2H- 501.2yl)-carbonyloxy] pyridinyl 110 CO₂Me (RS)-[(Pyrrolidin-1-4-phenyl-piperazinyl 504.3 yl)-carbonyloxy] 111 H (RS)-(Benzoyl-4-phenyl-3,6-dihydro-2H- 463.2 methyl-amino) pyridinyl 112 H(RS)-(Benzoyl- 4-phenyl-piperazinyl 466.2 methyl-amino) 113 H(RS)-[Isopropyl- 4-phenyl-piperazinyl 448.3 oxocarbonyl- (methyl)amino]461 Me 5,5-difluoro 4-(4-cyano-3,5- 433.1 dimethylphenyl)-3,6-dihydropyridin-1(2H)-yl 462 H 5,5-difluoro 4-(4-cyano-3,5- 419.1dimethylphenyl)-3,6- dihydropyridin-1(2H)-yl 463 Me 5,5-difluoro4-(3-isopropylphenyl-3,6- 422.2 dihydropyridin-1(2H)-yl 464 H5,5-difluoro 4-(3-isopropylphenyl-3,6- 408.2 dihydropyridin-1(2H)-yl 465Me 5,5-difluoro 4-[(2-methylquinolin-4- 485.1 yl)methoxy]phenylamino 466H 5,5-difluoro 4-[(2-methylquinolin-4- 471.1 yl)methoxy]phenylamino 468H (5R)-F 4-[(2-methylquinolin-4- 453.0 yl)methoxy]phenylamino 471 Me(5R)-F (3R)-phenylpyrrolidin-1-yl 350.1 472 H (5R)-F(3R)-phenylpyrrolidin-1-yl 336.1 484 H (5R)-F 4-(4-cyano-3,5- 401.2dimethylphenyl)-3,6- dihydropyridin-1(2H)-yl 485 H (5R)-F4-(3-isopropylphenyl-3,6- 390.2 dihydropyridin-1(2H)-yl 486 Me (5R)-F4-(4-cyano-3,5- 415.2 dimethylphenyl)-3,6- dihydropyridin-1(2H)-yl 487Me (5R)-F 4-(3-isopropylphenyl-3,6- 404.2 dihydropyridin-1(2H)-yl

TABLE 3

Ex. R R¹ QY MS  25 H (S)-Hydroxy 4-phenyl-3,6-dihydro- 345.12H-pyridinyl  26 H (S)-Hydroxy 4-phenyl-piperidinyl 347.1  27 H(S)-Hydroxy 4-phenyl-piperazinyl 348.1  28 H (S)-Hydroxy3-phenyl-2,5-dihydro- 331.1 pyrrolyl  29 H (RS)-pyrrolidinl-yl(3R)-phenyl-pyrrolidinyl 386.2  31 H (R)-[Morpholin-4-yl](3R)-phenyl-pyrrolidinyl 402.2  30 H (S)-[Morpholin-4-yl](3R)-phenyl-pyrrolidinyl 402.2  32 H (RS)-[(3R)-Hydroxy-(3R)-phenyl-pyrrolidinyl 402.2 pyrrolidin-1-yl]  33 H (S)-Hydroxy[4-(4-tert-Butyl-phenyl)- 404.2 piperazinyl  34 H(RS)-[tetrahydro-furan- (3R)-phenyl-pyrrolidinyl 460.2 (3S)-yloxocarbonyl (methyl)amino]  35 H (RS)-[tetrahydro-furan-(3R)-phenyl-pyrrolidinyl 460.2 (3R)-yl oxocarbonyl (methyl)amino]  36 H(RS)-[tetrahydro-2H-pyran-4- (3R)-phenyl-pyrrolidinyl 474.2 yloxocarbonyl (methyl)amino]  37 H (S)-[Pyrrolidin-1-yl(3R)-phenyl-pyrrolidinyl 430.3 carbonyloxy]  38 H (S)-[Methylamino-(3R)-phenyl-pyrrolidinyl 390.2 carbonyloxy]  39 H (S)-[Dimethylamino-(3R)-phenyl-pyrrolidinyl 404.3 carbonyloxy]  40 H (S)-[(Morpholin-4-yl)-(3R)-phenyl-pyrrolidinyl 446.2 carbonyloxy]  41 H (S)-[(3R)-Hydroxy-(3R)-phenyl-pyrrolidinyl 446.3 pyrrolidin-1-yl]- carbonyloxy  50 H(RS)-(2-Oxo-2-piperidin-1- 4-phenyl-piperazinyl 457   yl-ethyl)  51 H(RS)-(2-Oxo-2-pyrrolidin- 4-phenyl-piperazinyl 443   1-yl-ethyl)  52 H(RS)-{2-Oxo-2-[(3R)- 4-phenyl-piperazinyl 459   hydroxypyrrolidin-1-yl]-ethyl}  53 H (RS)-(2-Oxo-2-piperidin-1- [4-(2-methyl-quinolin-4- 559  yl-ethyl) ylmethoxy)-phenyl]- amino  59 H (RS)-[2-(4-Methyl-4-phenyl-piperazinyl 472.2 piperazin-1-yl)-2-oxo- ethyl]  60 H(RS)-(2-Morpholin-4-yl-2- 4-phenyl-piperazinyl 459.2 oxo-ethyl)  61 H(RS)-[(2-Methoxy- 4-phenyl-piperazinyl 447.2 ethylcarbamoyl)-methyl]  62H (S)-[Methylamino- 4-phenyl-piperazinyl 405.1 carbonyloxy]  63 H(S)-[Dimethylamino- 4-phenyl-piperazinyl 419.1 carbonyloxy]  64 H(S)-[(Pyrrolidin-1-yl)- 4-phenyl-piperazinyl 445.1 carbonyloxy]  65 H(S)-[(Piperidin-1-yl)- 4-phenyl-piperazinyl 459.2 carbonyloxy]  66 H(S)-[(Morpholin-4-yl)- 4-phenyl-piperazinyl 461.1 carbonyloxy]  67 H(S)-{[(3R)-Hydroxy- 4-phenyl-piperazinyl 461.1 pyrrolidin-1-yl]-carbonyloxy}  68 H (S)-[Cyclopropylamino- 4-phenyl-piperazinyl 431.1carbonyloxy]  72 H (R)-[(Pyrrolidin-1-yl)- (3R)-phenyl-pyrrolidinyl430.2 carbonyloxy]  73 H (R)-[(Morpholin-4-yl)- (3R)-phenyl-pyrrolidinyl446.2 carbonyloxy]  74 H (R)-[Dimethylamino- (3R)-phenyl-pyrrolidinyl404.2 carbonyloxy]  75 H (R)-[Methylamino- (3R)-phenyl-pyrrolidinyl390.2 carbonyloxy]  76 H (S)-[Methoxy- (3R)-phenyl-pyrrolidinyl 390.1carbonylamino]  77 H (R)-Methanesulfonylamino (3R)-phenyl-pyrrolidinyl410.1  78 H (R)-Acetylamino (3R)-phenyl-pyrrolidinyl 374.2  83 H(S)-(2-oxo-2-piperidin-1- 4-(3-Isopropyl-phenyl)- 498.3 yl-ethyl)piperidinyl  83 H (R)-(2-oxo-2-piperidin-1- 4-(3-Isopropyl-phenyl)-498.3 yl-ethyl) piperidinyl  92 H (RS)-(2-Oxo-2-piperidin-1-4-phenyl-piperazinyl 457   yl-ethyl) 115 n-Pr (S)-Hydroxy(3R)-phenyl-pyrrolidinyl 375.2 115 n-Pr (R)-Hydroxy(3R)-phenyl-pyrrolidinyl 375.2 116 H (S)-Methylamino-4-(4-tert-butyl-phenyl)- 461.3 carbonyloxy piperazinyl 117 H(S)-Dimethylamino- 4-(4-tert-butyl-phenyl)- 475.3 carbonyloxypiperazinyl 118 H (S)-Cyclopropylamino- 4-(4-tert-butyl-phenyl)- 487.3carbonyloxy piperazinyl 119 H (S)-(Pyrrolidin-1-yl4-(4-tert-butyl-phenyl)- 501.3 carbonyloxy) piperazinyl 120 H (S-[(3R)-4-(4-tert-butyl-phenyl)- 517.3 Hydroxypyrrolidin-1-yl piperazinylcarbonyloxy] 121 H (S)-(Morpholin-4-yl 4-(4-tert-butyl-phenyl)- 517.3carbonyloxy) piperazinyl 122 H (S)-(Piperidin-1-yl4-(4-tert-butyl-phenyl)- 515.3 carbonyloxy) piperazinyl 123 H(R)-Methylamino- 4-phenyl-3,6-dihydro- 402.1 carbonyloxy 2H-pyridinyl124 H (R)-Dimethylamino- 4-phenyl-3,6-dihydro- 416.1 carbonyloxy2H-pyridinyl 125 H (R)-(Pyrrolidin-1-yl 4-phenyl-3,6-dihydro- 442.1carbonyloxy) 2H-pyridinyl

TABLE 4

Ex. R QY MS  12 [Tetrahydro-pyran-4-yl]-oxo- (3R)-phenyl-pyrrolidinyl446.1 carbonyl  13 [(3R)-tetrahydro-furan-3-yl]-oxy-(3R)-phenyl-pyrrolidinyl 432.1 carbonyl  14[(3S)-tetrahydro-furan-3-yl]-oxy- (3R)-phenyl-pyrrolidinyl 432.1carbonyl  15 2-methoxy-ethyloxy-carbonyl (3R)-phenyl-pyrrolidinyl 420.1 16 [tetrahydro-pyran-4-yl]-oxo- 4-phenyl-piperazinyl 461.2 carbonyl  17[(3R)-tetrahydro-furan-3-yl]-oxo- 4-phenyl-piperazinyl 447.1 carbonyl 18 [(3S)-tetrahydro-furan-3-yl]-oxo- 4-phenyl-piperazinyl 447.2carbonyl  19 2-methoxy-ethyloxy-carbonyl 4-phenyl-piperazinyl 435.1  20[tetrahydro-pyran-4-yl]-oxo- 4-phenyl-piperidinyl 460.2 carbonyl  21[(3R)-tetrahydro-furan-3-yl]-oxo- 4-phenyl-piperidinyl 446.2 carbonyl 22 [(3S)-tetrahydro-furan-3-yl]-oxo- 4-phenyl-piperidinyl 446.2carbonyl  23 2-methoxy-ethyloxy-carbonyl 4-phenyl-piperidinyl 444.2  69Morpholine-4-carbonyl 4-phenyl-piperidinyl 445.2  79piperidine-1-carbonyl 4-phenyl-piperidinyl 443.2  80pyrrolidine-1-carbonyl 4-phenyl-piperidinyl 429.2  984-trifluoromethoxy-benzoyl (3R)-phenyl-pyrrolidinyl 506.2  994-trifluoromethoxy- (3R)-phenyl-pyrrolidinyl 542.0 benzenesulfonyl 1003-trifluoromethoxy-benzoyl (3R)-phenyl-pyrrolidinyl 506.2 1012-trifluoromethoxy-benzoyl (3R)-phenyl-pyrrolidinyl 506.0 1024-Difluoromethoxy-benzoyl (3R)-phenyl-pyrrolidinyl 488.2

TABLE 5

Ex. R R¹ QY MS 126 CO₂Me 3-fluorophenoxy 4-phenylpiperazin-1-yl 501.2 127 CO₂Me 3-(trifluoromethyl)phenoxy 4-phenylpiperazin-1-yl 551.1  128CO₂Me 2,4-difluorophenoxy 4-phenylpiperazin-1-yl 519.0  129 CO₂Me3-chloro-4-fluorophenoxy 4-phenylpiperazin-1-yl 535.0  130 CO₂Me5-chloropyridin-3-yl)oxy 4-phenylpiperazin-1-yl 518.1  131 CO₂Me3-bromophenoxy 4-phenylpiperazin-1-yl 561.0  132 CO₂Me Pyridin-3-yloxy4-phenylpiperazin-1-yl 484.1  133 CO₂Me Quinolin-6-yloxy4-phenylpiperazin-1-yl 534.1  134 CO₂Me 3-methylphenoxy4-phenylpiperazin-1-yl 497.1  135 CO₂Me 3-methoxyphenoxy4-phenylpiperazin-1-yl 513.1  136 CO₂Me (6-methylpyridin-2-yl)oxy4-phenylpiperazin-1-yl 498.1  137 CO₂Me (2-methylquinolin-4-yl)oxy4-phenylpiperazin-1-yl 548.15 138 CO₂Me phenoxy 4-phenylpiperazin-1-yl483.2  139 CO₂Me 3-chlorophenoxy 4-phenylpiperazin-1-yl 517.0  140 CO₂Me2,3-difluorophenoxy 4-phenylpiperazin-1-yl 519.1  141 CO₂MePyridin-2-yloxy 4-phenylpiperazin-1-yl 484.1  142 CO₂Me Quinolin-4-yloxy4-phenylpiperazin-1-yl 534.1  143 CO₂Me Pyridin-4-yloxy4-phenylpiperazin-1-yl 484.05 144 CO₂Me (4-methylpyridin-2-yl)oxy4-phenylpiperazin-1-yl 498.2  145 CO₂Me 2-fluorophenoxy4-phenylpiperazin-1-yl 501.1  146 CO₂Me 2-methylphenoxy4-phenylpiperazin-1-yl 497.1  147 CO₂Me 4-fluorophenoxy4-phenylpiperazin-1-yl 501.1  148 CO₂Me 3,5-difluorophenoxy4-phenylpiperazin-1-yl 519.0  150 CO₂Me 1,3-benzothiazol-2-yl4-phenylpiperazin-1-yl 540.1  151 CO₂Me 3,4-difluorophenoxy4-phenylpiperazin-1-yl 519.0  152 Me Pyridin-4-yloxy 4-phenyl-3,6-437.1  dihydropyridin-1(2H)-yl 153 Me (4-methylpyridin-2-yl)oxy4-phenyl-3,6- 451.1  dihydropyridin-1(2H)-yl 154 Me Phenoxy4-phenyl-3,6- 436.0  dihydropyridin-1(2H)-yl 155 Me 3-fluorophenoxy4-phenyl-3,6- 454.1  dihydropyridin-1(2H)-yl 156 Me Quinolin-6-yloxy4-phenyl-3,6- 487.0  dihydropyridin-1(2H)-yl 157 Me(2-methylquinolin-4-yl)oxy 4-phenyl-3,6- 501.1  dihydropyridin-1(2H)-yl158 Me Pyridin-2-yloxy 4-phenyl-3,6- 437.0  dihydropyridin-1(2H)-yl 159Me 3,5-difluorophenoxy 4-phenyl-3,6- 472.1  dihydropyridin-1(2H)-yl 160Me Quinolin-4-yloxy 4-phenyl-3,6- 486.9  dihydropyridin-1(2H)-yl 161 MePyridin-4-yloxy 4-phenylpiperidin-1-yl 439.2  162 Me (2-methyl-1,2,3,4-4-phenylpiperidin-1-yl 507.2  tetrahydroquinolin-4-yl)oxy 163 Me(4-methylpyridin-2-yl)oxy 4-phenylpiperidin-1-yl 453.0  164 MePyridin-2-yloxy 4-phenylpiperidin-1-yl 439.1  165 MeS02 phenoxy4-phenylpiperazin-1-yl 503.2  166

phenoxy 4-phenylpiperazin-1-yl 539.2  167 CO₂Me 2-bromophenoxy4-phenylpiperazin-1-yl 168 CO₂Me 2-chlorophenoxy 4-phenylpiperazin-1-yl517.2  169

phenoxy 4-phenylpiperazin-1-yl 553.2  170 CO₂Et phenoxy4-phenylpiperazin-1-yl 497.2  171 H 3-methylphenoxy4-phenylpiperazin-1-yl 439.1  172 H 3-(trifluoromethyl)pheoxy4-phenylpiperazin-1-yl 493.2  173 H 3-chlorophenoxy4-phenylpiperazin-1-yl 459.2  174 H 3-methoxyphenoxy4-phenylpiperazin-1-yl 455.0  175 H 3-fluorophenoxy4-phenylpiperazin-1-yl 443.2  176 Me (piperidin-1-ylcarbonyl)oxy4-phenyl-3,6- 471.1  dihydropyridin-1(2H)-yl 177 Me[(2S)-2-(hydroxymethyl)pyrrolidin- 4-phenyl-3,6- 487.151-yl]-carbonyloxy dihydropyridin-1(2H)-yl 178 Me Azepan-1-yl-carbonyloxy4-phenyl-3,6- 485.2  dihydropyridin-1(2H)-yl 179 MeAzetidin-1-yl-carbonyloxy 4-phenyl-3,6- 443.2  dihydropyridin-1(2H)-yl180 Me [(dimethylamino)carbonyl]oxy 4-phenyl-3,6- 431.1 dihydropyridin-1(2H)-yl 181 Me 2,5-dihydro-1H-pyrrol-1-yl- 4-phenyl-3,6-455.1  carbonyloxy dihydropyridin-1(2H)-yl 182 Me(pyrrolidin-1-ylcarbonyl)oxy 4-phenyl-3,6- 457.1 dihydropyridin-1(2H)-yl 183 Me Azetidin-1-yl-carbonyloxy4-phenylpiperazin-1-yl 446.2  184 Me Azetidin-1-yl-carbonyloxy3-phenyl-2,5-dihydro-1H- 429.2  pyrrol-1-yl 185 MeAzetidin-1-yl-carbonyloxy 1,3-dihydro-2H- 453.2  benzo[e]isoindol-2-yl186 Me (pyrrolidin-1-ylcarbonyl)oxy 4-phenylpiperazin-1-yl 460.2  187 MeAzetidin-1-yl-carbonyloxy (3R)-3-phenylpyrrolidin- 431.2  1-yl 188 Me(piperidin-1-ylcarbonyl)oxy 4-phenylpiperazin-1-yl 474.2  189 MeAzetidin-1-yl-carbonyloxy 1,3-dihydro-2H-isoindol- 402.2  2-yl 190 Me(pyrrolidin-1-ylcarbonyl)oxy 3-phenyl-2,5-dihydro-1H- 443.05 pyrrol-1-yl191 Me (pyrrolidin-1-ylcarbonyl)oxy 4-phenylpiperidin-1-yl 459.15 192 MeAzepan-1-yl-carbonyloxy 4-phenylpiperidin-1-yl 487.2  193 Me[(2S)-2-(hydroxymethyl)pyrrolidin- 4-phenylpiperidin-1-yl 489.2 1-yl]-carbonyloxy 194 Me (piperidin-1-ylcarbonyl)oxy4-phenylpiperidin-1-yl 473.2  195 Me [(dimethylamino)carbonyl]oxy4-phenylpiperidin-1-yl 433.1  196 CO₂Me[(2S)-2-(hydroxymethyl)pyrrolidin- 4-phenylpiperazin-1-yl 534.2 1-yl]-carbonyloxy 197 CO₂Me (pyrrolidin-1-ylcarbonyl)oxy1,3-dihydro-2H-isoindol- 461.2  2-yl 198 CO₂Me(piperidin-1-ylcarbonyl)oxy 4-phenylpiperazin-1-yl 518.15 199 CO₂Me(pyrrolidin-1-ylcarbonyl)oxy 4-phenylpiperazin-1-yl 504.2  200 CO₂Me(pyrrolidin-1-ylcarbonyl)oxy (3R)-3-phenylpyrrolidin- 489.2  1-yl 201CO₂Me [(dimethylamino)carbonyl]oxy 4-phenylpiperazin-1-yl 478.1  202CO₂Me (pyrrolidin-1-ylcarbonyl)oxy 4-phenyl-3,6- 501.2 dihydropyridin-1(2H)-yl 203 CO₂Me (pyrrolidin-1-ylcarbonyl)oxy4-phenylpiperidin-1-yl 503.2  204 H (pyrrolidin-1-ylcarbonyl)oxy4-phenyl-3,6- 443.2  dihydropyridin-1(2H)-yl 205 HAzetidin-1-yl-carbonyloxy 1,3-dihydro-2H- 439.2  benzo[e]isoindol-2-yl206 H Azetidin-1-yl-carbonyloxy 1,3-dihydro-2H-isoindol- 389.2  2-yl 207H Azetidin-1-yl-carbonyloxy 4-phenyl-3,6- 429.2  dihydropyridin-1(2H)-yl208 H Azetidin-1-yl-carbonyloxy (3R)-3-phenylpyrrolidin- 417.2  1-yl 209H Azetidin-1-yl-carbonyloxy 4-phenylpiperazin-1-yl 432.2  210 HAzetidin-1-yl-carbonyloxy 3-phenyl-2,5-dihydro-1H- 415.2  pyrrol-1-yl211 H Azetidin-1-yl-carbonyloxy 4-phenylpiperidin-1-yl 431.3  212 H(pyrrolidin-1-ylcarbonyl)oxy 4-phenylpiperidin-1-yl 445.2  213 CO₂Me2-oxo-2-pyrrolidin-1-ylethoxy 4-phenylpiperazin-1-yl 518.2  214 CO₂Mephenylthio 4-phenylpiperazin-1-yl 499.1  215 CO₂Me Allyloxy4-phenylpiperazin-1-yl 447.1  216 CO₂Me propoxy 4-phenylpiperazin-1-yl449.2  217 CO₂Me methoxy 4-phenylpiperazin-1-yl 421.2  218 H tert-butoxy4-phenylpiperazin-1-yl 405.1  219 CO₂Me tert-butoxy4-phenylpiperazin-1-yl 463.2  248 H 2-oxo-2-pyrrolidin-1-ylethyl4-(4-cyano-2- 482.1  methylphenyl)piperidin- 1-yl 249 H Methyl-carbamicacid isopropyl 4-phenylpiperidin-1-yl 447.1  ester 413 Me

4-phenylpiperazin-1-yl 458.1  414 Me

4-phenylpiperazin-1-yl 488.1  415 Me

4-phenylpiperazin-1-yl 434.1  416 Me

4-phenylpiperazin-1-yl 502.2  417 Me 2-fluorophenoxy4-phenylpiperazin-1-yl 457.2  418 Me (6-methylpyridin-2-yl)oxy4-phenylpiperazin-1-yl 454.2  419 Me Pyridin-4-yloxy4-phenylpiperazin-1-yl 440.1  420 Me 3-fluorophenoxy4-phenylpiperazin-1-yl 457.2  421 Me Pyridine-2-yloxy4-phenylpiperazin-1-yl 440.2  422 Me 1,3-benzothiazol-2-yloxy4-phenylpiperazin-1-yl 423 Me 3-methylphenoxy 4-phenylpiperazin-1-yl453.2  424 Me (4-methylpyridin-2-yl)oxy 4-phenylpiperazin-1-yl 454.2 425 Me 3,4-difluorophenoxy 4-phenylpiperazin-1-yl 475.1  426 Me2-chlorophenoxy 4-phenylpiperazin-1-yl 473.2  427 Me

4-phenylpiperazin-1-yl 496.1  428 CO₂Me Quinolin-6-yloxy4-phenylpiperazin-1-yl 534.2  429 Me Pyridine-3-yloxy3-phenyl-2,5-dihydro-1H- 423.1  pyrrol-1-yl 430 Me Pyridine-4-yl3-phenyl-2,5-dihydro-1H- 423.0  pyrrol-1-yl 431 Me 3-fluorophenoxy3-phenyl-2,5-dihydro-1H- 440.1  pyrrol-1-yl 432 Me phenoxy3-phenyl-2,5-dihydro-1H- 422.1  pyrrol-1-yl 433 Me Pyridine-2-yloxy3-phenyl-2,5-dihydro-1H- 423.1  pyrrol-1-yl 434 Me(4-methylpyridin-2-yl)oxy 3-phenyl-2,5-dihydro-1H- 437.1  pyrrol-1-yl435 Me (6-methylpyridin-2-yl)oxy 3-phenyl-2,5-dihydro-1H- 437.1 pyrrol-1-yl 436 Me Pyridine-2-yloxy 4-phenylpiperazin-1-yl 440.2  437 MePyridine-3-yloxy 4-phenylpiperazin-1-yl 440.1  438 Me(2-methylquinolin-4-yl)oxy 4-phenylpiperazin-1-yl 504.2  439 Me(2-methylquinolin-4-yl)oxy 3-phenyl-2,5-dihydro-1H- 487.2  pyrrol-1-yl440 Me quinolin-4-yloxy 4-phenylpiperazin-1-yl 490.3  441 Mequinolin-6-yloxy 3-phenyl-2,5-dihydro-1H- 473.1  pyrrol-1-yl 442 Mequinolin-4-yloxy 3-phenyl-2,5-dihydro-1H- 473.1  pyrrol-1-yl 443 HPyridine-2-yloxy 4-phenylpiperazin-1-yl 426.1  444 Me(4-methylpyridin-2-yl)oxy 4-phenylpiperazin-1-yl 454.2  445 H(5-chloropyridin-3-yl)oxy 4-(4-cyano-3,5- 510.1  dimethylphenyl)-3,6-dihydropyridin-1(2H)-yl 446 H (6-methylpyridin-2-yl)oxy 4-(4-cyano-3,5-490.1  dimethylphenyl)-3,6- dihydropyridin-1(2H)-yl 447 H(4-methylpyridin-2-yl)oxy 4-(4-cyano-3,5- 490.2  dimethylphenyl)-3,6-dihydropyridin-1(2H)-yl 448 H Pyridin-2-yloxy 4-(4-cyano-3,5- 476.2 dimethylphenyl)-3,6- dihydropyridin-1(2H)-yl 449 H phenoxy4-(4-cyano-3,5- 475.2  dimethylphenyl)-3,6- dihydropyridin-1(2H)-yl 450H Pyridin-2-yloxy 4-phenyl-3,6- 423.1  dihydropyridin-1(2H)-yl 451 H(3-methyl-1H-pyrazol-5-yl)oxy 4-(4-cyano-3,5- dimethylphenyl)-3,6-dihydropyridin-1(2H)-yl 452 H (5-methylisoxazol-3-yl)oxy(3R)-phenylpyrrolidin-1- 415.1  yl 453 H (3-methyl-1H-pyrazol-5-yl)oxy(3R)-phenylpyrrolidin-1- 414.1  yl 454 H (5-chloropyridin-3-yl)oxy(3R)-phenylpyrrolidin-1- 445.1  yl 455 H (4-methylpyridin-2-yl)oxy(3R)-phenylpyrrolidin-1- 425.0  yl 456 H Pyridin-2-yloxy(3R)-phenylpyrrolidin-1- 411.1  yl 457 H 3,4-difluorophenoxy4-(4-cyano-3,5- 511.1  dimethylphenyl)-3,6- dihydropyridin-1(2H)-yl 458H (5-methylisoxazol-3-yl)oxy 4-(4-cyano-3,5- 480.1  dimethylphenyl)-3,6-dihydropyridin-1(2H)-yl 459 H (2-methylquinolin-4-yl)oxy 4-(4-cyano-3,5-540.1  dimethylphenyl)-3,6- dihydropyridin-1(2H)-yl 460 H(2-methylquinolin-4-yl)oxy (3R)-phenylpyrrolidin-1- 475.1  yl 467 H

(4-[(2-methylquinolin-4- yl)methoxy]phenylamino) 576.2  469 Me

(4-[(2-methylquinolin-4- yl)methoxy]phenylamino) 590.2  470 H

4-(4-cyano-3,5- dimethylphenyl)-3,6- dihydropyridin-1(2H)-yl 524.2  473H phenoxy 3-phenyl-2,5-dihydro-1H- 408.2  pyrrol-1-yl 474 HPyridin-2-yloxy 3-phenyl-2,5-dihydro-1H- 409.2  pyrrol-1-yl 475 HPyridin-4-yloxy 3-phenyl-2,5-dihydro-1H- 409.2  pyrrol-1-yl 476 HPyridin-3-yloxy 3-phenyl-2,5-dihydro-1H- 409.2  pyrrol-1-yl 477 H(6-methylpyridin-2-yl)oxy 3-phenyl-2,5-dihydro-1H- 423.2  pyrrol-1-yl478 H (4-methylpyridin-2-yl)oxy 3-phenyl-2,5-dihydro-1H- 423.2 pyrrol-1-yl 479 H 3-fluorophenoxy 3-phenyl-2,5-dihydro-1H- 426.2 pyrrol-1-yl 480 H Quinolin-6-yloxy 3-phenyl-2,5-dihydro-1H- 459.2 pyrrol-1-yl 481 H Quinolin-7-yloxy 3-phenyl-2,5-dihydro-1H- 459.2 pyrrol-1-yl 482 H Quinolin-4-yloxy 3-phenyl-2,5-dihydro-1H- 459.2 pyrrol-1-yl 483 H (2-methylquinolin-4-yl)oxy 3-phenyl-2,5-dihydro-1H-473.2  pyrrol-1-yl

TABLE 6

Ex. R QY MS 220 (E)-(cyanoimino)- (3R)-phenylpyrrolidin-1-yl 439.2pyrrolidin-1-yl)methyl 221 (E)-azetidin-1- (3R)-phenylpyrrolidin-1-yl425.2 yl(cyanoimino)methyl 222 (E)-(cyanoimino)-(3R)-phenylpyrrolidin-1-yl 413.2 (dimethylamino)methyl 223(E)-(cyanoimino)- (3R)-phenylpyrrolidin-1-yl 425.2(cyclopropylamino)methyl 224 (E)-(cyanoimino)-(3R)-phenylpyrrolidin-1-yl 453.3 (piperidin-1-yl)methyl 225(Z)-(cyanoimino)- (3R)-phenylpyrrolidin-1-yl 455.3(morpholin-4-yl)methyl 226 (Z)-(cyanoimino)- (3R)-phenylpyrrolidin-1-yl401.1 (hydroxyamino)methyl 227 (E)-azepan-1-yl-(3R)-phenylpyrrolidin-1-yl 467.3 (cyanoimino)methyl 228(Z)-(cyanoimino)(4-meth- (3R)-phenylpyrrolidin-1-yl 468.2ylpiperazin-1-yl)methyl 229 (Z)-cyanoimino)(thio-(3R)-phenylpyrrolidin-1-yl 471.1 morpholin-4-yl)methyl 230(E)-(cyanoimino)(4-meth- (3R)-phenylpyrrolidin-1-yl 467.2ylpiperidin-1yl)methyl 231 (Z)-(cyanoimino)(2,5-dihydro-(3R)-phenylpyrrolidin-1-yl 437.2 1H-pyrrol-1-yl)methyl 232(Z)-(cyanoimino)(1,3-dihydro- (3R)-phenylpyrrolidin-1-yl 487.12H-isoindol-2-yl)methyl 233 (Z)-(cyanoimino)(3,4-dihydro-(3R)-phenylpyrrolidin-1-yl 487.1 isoquinolin-2(1H)-yl)methyl 234(Z)-1-(hydroxyamino)- (3R)-phenylpyrrolidin-1-yl 442.2 2-nitrovinyl 235(E)-(cyanoimino)(piperidin- 4-(4-cyano-2-methyl- 507 1-yl)methylphenyl)piperazin-1-yl) 236 (E)-(cyanoimino)- 4-(4-cyano-2-methyl- 467(dimethylamino)methyl phenyl)piperazin-1-yl) 237 (E)-azepan-1-4-(4-cyano-2-methyl- 521 yl(cyanoimino)methyl phenyl)piperazin-1-yl) 238(E)-(cyanoimino)- 4-(4-cyano-2-methyl- 493 pyrrolidin-1-yl)methylphenyl)piperazin-1-yl) 239 (E)-(cyanoimino)(cyclo- 4-(4-cyano-2-methyl-479 propylamino)methyl phenyl)piperazin-1-yl) 240 (E)-azetidin-1-l4-(4-cyano-2-methyl- 479 yl(cyanoimino)methy phenyl)piperazin-1-yl) 501(E)-(Cyanoimino)(cyclo- 4-(4-cyano-2-methylphenyl)- 476.2propylamino)methyl 3,6-dihydropyridin-1(2H)-yl 502 (E)-(Cyanoimino)(di-4-(4-cyano-2-methylphenyl)- 464.2 methylamino)methyl3,6-dihydropyridin-1(2H)-yl 503 (E)-(Cyanoimino)- 4-(4-cyano-2-methyl-507.2 (piperidin-1-yl)methyl phenyl)piperazin-1-yl) 504 (E)-azetidin-1-4-(4-cyano-2-methylphenyl)- 476.1 yl(cyanoimino)methyl3,6-dihydropyridin-1(2H)-yl 505 (E)-azetidin-1- 4-(4-cyano-2-methyl-478.1 yl(cyanoimino)methyl phenyl)piperidin-1-yl 506 (E)-(Cyanoimino)-4-(4-cyano-2-methylphenyl)- 490.2 (pyrrolidin-1-yl)methyl3,6-dihydropyridin-1(2H)-yl 507 (E)-(Cyanoimino)-4-(4-cyano-2-methylphenyl)- 504.2 (piperidin-1-yl)methyl3,6-dihydropyridin-1(2H)-yl 508 (E)-(Cyanoimino)- 4-(4-cyano-2-methyl-506.2 (piperidin-1-yl)methyl phenyl)piperidin-1-yl

TABLE 7

Ex. R R¹ QY MS 241

4-phenylpiperazin-1-yl 420.1 242

4-phenylpiperazin-1-yl 384.1 243 (5S) CH₂Ph OH 4-phenylpiperazin-1-yl438.1 244 (5R) Ph OH 4-phenylpiperazin-1-yl 424.1 245 (5R) CH₂Ph OH4-phenylpiperazin-1-yl 438.1 246 (5R) iPr OH 4-phenylpiperazin-1-yl390.1 247

OH 4-phenylpiperazin-1-yl 388.1 250

H 4-phenyl-3,6- dihydropyridin-1(2H)-yl 426.2 251

H 4-phenylpiperazin-1-yl 514.3 252

H 4-phenylpiperazin-1-yl 443.1 253

H 4-phenylpiperazin-1-yl 443.1 254

H 4-phenylpiperazin-1-yl 429.1 255

H 4-phenylpiperazin-1-yl 429.1 256

H 4-phenylpiperazin-1-yl 445.2 257

H 4-phenylpiperazin-1-yl 540.2 258

H 4-phenylpiperazin-1-yl 540.2 259

H (3R)-phenylpyrrolidin-1-yl 430.1 260

H (3R)-phenylpyrrolidin-1-yl 404.1 261

H 4-phenyl-3,6- dihydropyridin-1(2H)-yl 458.1 262

H 4-phenyl-3,6- dihydropyridin-1(2H)-yl 442.1 263

H 4-phenyl-3,6- dihydropyridin-1(2H)-yl 402.1 264

H 4-phenyl-3,6- dihydropyridin-1(2H)-yl 416.1 265 (5R)-hydroxy H(3R)-phenylpyrrolidin-1-yl 333.1 266

H 4-phenyl-3,6- dihydropyridin-1(2H)-yl 416.1 267

H 4-phenyl-3,6- dihydropyridin-1(2H)-yl 442.1 268

H 4-phenyl-3,6- dihydropyridin-1(2H)-yl 402.1 269

H 4-phenyl-3,6- dihydropyridin-1(2H)-yl 458.1 270

H (3R)-phenylpyrrolidin-1-yl 390.1 271

H (3R)-phenylpyrrolidin-1-yl 446.1 272

H 4-phenylpiperidin-1-yl 444.2 273

H 4-phenylpiperidin-1-yl 459.2 274

H 4-phenylpiperidin-1-yl 445.2 275

H 4-phenylpiperidin-1-yl 419.2 276

H 4-phenylpiperidin-1-yl 405.2 277

H 4-phenyl-3,6- dihydropyridin-1(2H)-yl 442.1 278

H 4-phenyl-3,6- dihydropyridin-1(2H)-yl 402.1 279

H 4-phenyl-3,6- dihydropyridin-1(2H)-yl 416.1 280

H 4-phenylpiperidin-1-yl 418.2 281

H 4-phenylpiperidin-1-yl 458.2 282 (5R)-CH₃ OH 4-phenylpiperidin-1-yl362.1 283 (5R)-CH₃ OH 4-phenyl-3,6- 359.1 dihydropyridin-1(2H)-yl 284

H 4-phenylpiperazin-1-yl 461.2 285

H 4-phenylpiperazin-1-yl 286

H 4-phenylpiperazin-1-yl 447.2 287 (5R)-CH₂CH═CH₂ OH 4-phenyl-3,6- 385.2dihydropyridin-1(2H)-yl 288 (5R)-CH₂CH═CH₂ OH 4-phenylpiperazin-1-yl388.2 289 (5S)-CH₂CH═CH₂ OH 4-phenyl-3,6- 385.2 dihydropyridin-1(2H)-yl290 (5S)-CH₂CH═CH₂ OH 4-phenylpiperazin-1-yl 388.2 291 (5R)-CH₃ OH4-phenylpiperidin-1-yl 361.2 292 (5S)-CH₃ OH 4-phenylpiperidin-1-yl361.2 293 (5S)-CH₃ OH 4-phenylpiperazin-1-yl 362.2 294 (5R)-CH₂CH₂CH₃ OH4-phenyl-3,6- dihydropyridin-1(2H)-yl 295 (5S)-CH₂CH₂CH₃ OH4-phenyl-3,6- dihydropyridin-1(2H)-yl 296 (5R)-OPh H4-phenylpiperazin-1-yl 424.2 297

H 4-phenylpiperazin-1-yl 439.2 298 (5R)-(4-methylphenoxy) H4-phenylpiperazin-1-yl 438.1 299 (5R)-(2,3-difluorophenoxy) H4-phenylpiperazin-1-yl 460.1 300

H 4-phenylpiperazin-1-yl 439.2 301

H 4-phenylpiperazin-1-yl 489.2 302 (5R)-(3,4-difluorophenoxy) H4-phenylpiperazin-1-yl 460.2 303

H 4-phenylpiperazin-1-yl 459.1 304

H 4-phenylpiperazin-1-yl 509.0 305 (5R)-(2,4-dichlorophenoxy) H4-phenylpiperazin-1-yl 492.1 306

H 4-phenylpiperazin-1-yl 489.1 307

H 4-phenylpiperazin-1-yl 425.1 308 (5R)-(4-fluorophenoxy) H4-phenylpiperazin-1-yl 442.2 309

H 4-phenylpiperazin-1-yl 459.2 310

H 3-phenyl-2,5- dihydro-1-H-pyrrol-1-yl 442.2 311

H 4-phenylpiperazin-1-yl 475.2 312 (5R)-(2,3-dichlorophenoxy) H4-phenylpiperazin-1-yl 492.0 313 (5R)-benzyloxy H 4-phenylpiperazin-1-yl438.2 314

H 4-phenylpiperazin-1-yl 439.2 315 (5R)-(3-fluorophenoxy) H4-phenylpiperazin-1-yl 442.2 316

H 4-phenylpiperazin-1-yl 425.2 317

H 4-phenylpiperazin-1-yl 473.1 318

H 4-phenylpiperazin-1-yl 439.2 319 (5R)-[3,5-bis(trifluoromethyl) H4-phenylpiperazin-1-yl 560.2 phenoxy] 320 (5R)-(2-chlorophenoxy) H4-phenylpiperazin-1-yl 458.1 321 (5R)-(4-chlorophenoxy) H4-phenylpiperazin-1-yl 458.2 322 (5R)-(3-bromophenoxy) H4-phenylpiperazin-1-yl 502.1 323

H 4-phenylpiperazin-1-yl 481.1 324 (5R)-(3-chlorophenoxy) H4-phenylpiperazin-1-yl 458.2 325

H 4-phenylpiperazin-1-yl 426.2 326 (5R)-[3- H 4-phenylpiperazin-1-yl492.1 (trifluoromethyl)phenoxy] 327

H 4-phenylpiperazin-1-yl 475.2 328

H 4-phenylpiperazin-1-yl 481.2 329 (5R)- H 4-phenylpiperazin-1-yl 431.3[isobutyryl(methyl)amino] 330

H 4-phenylpiperidin-1-yl 430.2 331

H 4-phenylpiperidin-1-yl 418.1 332

H 4-phenylpiperidin-1-yl 404.1 333

H 4-phenylpiperidin-1-yl 432.1 334

H 4-phenylpiperidin-1-yl 428.1 335

H 4-phenylpiperidin-1-yl 336

H 4-phenylpiperidin-1-yl 473.2 337

H 4-phenylpiperidin-1-yl 390.2 338

H 4-phenylpiperazin-1-yl 488.3 339

H 4-phenylpiperazin-1-yl 461.2 340

H 4-phenylpiperazin-1-yl 523.3 341

H 4-phenylpiperazin-1-yl 487.3 342

H 4-phenylpiperazin-1-yl 511.3 343

H 4-phenylpiperazin-1-yl 493.2 344

H 4-phenylpiperazin-1-yl 493.2 345

H 4-phenylpiperazin-1-yl 507.3 346

H 4-phenylpiperazin-1-yl 445.2 347

H 4-phenylpiperazin-1-yl 546.3 348

H 4-phenylpiperazin-1-yl 461.2 349

H 4-phenylpiperazin-1-yl 489.2 350

H 4-phenylpiperazin-1-yl 449.2 351

H 4-phenylpiperazin-1-yl 482.2 352

H 4-phenylpiperazin-1-yl 482.2 353

H 4-phenylpiperazin-1-yl 482.2 354

H 4-phenylpiperazin-1-yl 355

H 4-phenylpiperazin-1-yl 459.2 356

H 4-phenylpiperazin-1-yl 473.3 357

H 4-phenylpiperazin-1-yl 532.3 358

H 4-phenylpiperazin-1-yl 607.3 359

H 4-phenylpiperazin-1-yl 475.2 360

H 4-phenylpiperazin-1-yl 502.3 361

H 4-phenylpiperazin-1-yl 502.2 362

H 4-phenylpiperazin-1-yl 475.2 363

H 4-phenylpiperazin-1-yl 475.2 364

H 4-phenylpiperazin-1-yl 489.3 365

H 4-phenylpiperazin-1-yl 475.2 366

H 4-phenylpiperazin-1-yl 503.3 367

H 4-phenylpiperazin-1-yl 489.3 368

H 4-phenylpiperazin-1-yl 511.2 369

H 4-phenylpiperazin-1-yl 449.2 370

H 4-phenylpiperazin-1-yl 463.2 371

H 4-phenylpiperazin-1-yl 477.2 372

H 4-phenylpiperazin-1-yl 449.2 373

H 4-phenylpiperazin-1-yl 525.3 374

H 4-phenylpiperazin-1-yl 491.2 375

H 4-phenylpiperazin-1-yl 488.2 376 (5R)-pyridin-3-ylmethoxy H4-phenylpiperazin-1-yl 439.3 377 (5R)- pyridin-2-yloxy H4-phenylpiperazin-1-yl 425.2 378 (5R)-quinolin-6-yloxy H4-phenylpiperazin-1-yl 475.2 379 (5R)-[(1-ethylpiperidin-4- H4-phenyl-3,6- yl)oxy] dihydropyridin-1(2H)-yl 380(5R)-(4-hydroxyphenoxy) H 4-phenylpiperazin-1-yl 440.1 381 (5R)-[(4- H4-phenylpiperazin-1-yl 460.2 methyoxycyclohexyl)oxy] 383 (5R)-[(4- H4-phenyl-3,6- 457.2 methoxycyclohexyl)oxy] dihydropyridin-1(2H)-yl 384(5R)-{[2- H 4-phenylpiperazin-1-yl 543.2 (trifluoromethyl)quinolin-4-yl]oxy} 385 (5R)-(quinolin-2-yloxy) H 4-phenylpiperazin-1-yl 475.2 386(5R)-(quinolin-3-yloxy) H 4-phenylpiperazin-1-yl 475.1 387(5R)-(quinolin-5-yloxy) H 4-phenylpiperazin-1-yl 475.1 388(5R)-(quinolin-7-yloxy) H 4-phenylpiperazin-1-yl 475.2 389(5R)-(quinolin-8-yloxy) H 4-phenylpiperazin-1-yl 475.1 390(5R)-(pyridine-2-yloxy) H 4-phenyl-3,6- 422.1 dihydropyridin-1(2H)-yl391 (5R)-(pyridine-4-yloxy) H 4-phenyl-3,6- 422.1dihydropyridin-1(2H)-yl 392 (5R)-(quinolin-6-yloxy) H 4-phenyl-3,6-472.1 dihydropyridin-1(2H)-yl 393 (5R)-[(1-ethylpiperidin-4- H4-phenylpiperidin-1-yl 458.3 yl)oxy] 394 (5R)-(pyridine-2-yloxy) H4-phenylpiperidin-1-yl 424.2 395 (5R)-(pyridine-4-yloxy) H4-phenylpiperidin-1-yl 424.2 396 (5R)-(quinolin-6-yloxy) H4-phenylpiperidin-1-yl 474.2 397 (5R)-(3-chlorophenoxy) H 4-phenyl-3,6-455.1 dihydropyridin-1(2H)-yl 398 (5R)-(3,4-difluorophenoxy) H4-phenyl-3,6- 457.1 dihydropyridin-1(2H)-yl 399(5R)-(2,3-difluorophenoxy) H 4-phenyl-3,6- 457.1 dihydropyridin-1(2H)-yl400 (5R)-(isoquinolin-1-yloxy) H 4-phenylpiperazin-1-yl 475.2 401(5R)-(isoquinolin-3-yloxy) H 4-phenylpiperazin-1-yl 475.2 402(5R)-(isoquinolin-5-yloxy) H 4-phenylpiperazin-1-yl 475.2 403(5R)-(isoquinolin-7-yloxy) H 4-phenylpiperazin-1-yl 475.2 404(5R)-(2-naphthyloxy) H 4-phenylpiperazin-1-yl 474.2 405(5R)-(2,4-difluorophenoxy) H 4-phenylpiperazin-1-yl 460.1 406(5R)-(3,5-difluorophenoxy) H 4-phenylpiperazin-1-yl 460.1 407(5R)-(3-chloro-4- H 4-phenylpiperazin-1-yl 476.1 fluorophenoxy) 408(5R)-(3,4-dichlorophenoxy) H 4-phenylpiperazin-1-yl 492.1 409(5R)-(3,5-dichlorophenoxy) H 4-phenylpiperazin-1-yl 492.1 410(5R)-(2,5-dioxopyrrolidin-1- H 4-phenylpiperazin-1-yl 429.2 yl) 411(5R)-(5,5-dimethyl-2,4- H 4-phenylpiperazin-1-yl 459.2dioxo-1,3-oxazolidin-3-yl) 412 (5R)-(3-methyl-2,5- H4-phenylpiperazin-1-yl dioxoimidazolidin-1-yl) 488

4-(4-cyano-2- methylphenyl)piperazin-1- yl 459.2 489

4-(4-cyano-2- methylphenyl)piperazin-1- yl 423.2 490

(3R)-phenylpyrrolidin-1-yl 405.2 491 (5S)-isobutyl OH 4-phenyl-3,6-423.2 dihydropyridin-1(2H)-yl (M + Na) 492 (5S)-butyl OH 4-phenyl-3,6-401.2 dihydropyridin-1(2H)-yl 493

Me 4-phenylpiperazin-1-yl 445.2 494

Me 4-phenylpiperazin-1-yl 481.2 495 (5S)-isobutyl OH4-phenylpiperazin-1-yl 404.0 496 (5R)-cyclopropylmethyl OH4-phenylpiperazin-1-yl 402.1 497 butyl OH 4-phenylpiperazin-1-yl 404.2498

Me 4-phenylpiperazin-1-yl 459.2 499

(3R)-phenylpyrrolidin-1-yl 369.2 500 ethyl OH 4-phenylpiperazin-1-yl376.2

Biological Experimental Procedures

The capacity of the novel compounds of the invention to inhibit TNFα, orinhibit MMP function i.e., sheddase inhibition can be determined using asuitable screen (e.g., high through-put assay). For example, an agentcan be tested in an extracellular acidification assay, calcium fluxassay, ligand binding assay or chemotaxis assay. For example, thecapacity of the compounds of general formula (I) to act as inhibitors ofthe production of TNFα may be determined using the following procedure.A 100 μM solution of the inhibitor being tested or dilutions thereof isincubated at 37° C. in an atmosphere of 5% CO₂ with THP-1 cells (humanmonocytes) suspended in RPM1 1640 medium and 20 μM β-mercaptoethanol ata cell density of 1×10⁶/ml and stimulated with LPS. After 18 hours thesupernatant is assayed for the levels of TNFα using a commerciallyavailable ELISA kit. The activity in the presence of 0.1 mM inhibitor ordilutions thereof is compared to activity in a control devoid ofinhibitor and results reported as that inhibitor concentration effecting50% inhibition of the production of TNFα.

Example 509 PBMC Assay Measuring TNFα Activity

A leukophoresis (Biological Specialties, Colmar Pa.) was obtained fromnormal drug-free (no aspirin, ibuprofen, NSAIDs, etc.) donors. In a 50ml conical tube (VWR, NJ), there was added 20 mls of blood and 20 mls ofsterile 0.9% saline (Baxter Healthcare, Dearfield, Ill.) and mixed well.Underlay 10 mls of endotoxin free ficoll paque (Pharmacia, Uppsala,Sweden) and spinned at 3000 RPM for 30 minutes. The layer of white bloodcells was removed and washed with 50 mls 0.9% saline. Cells are thencounted and there is added 0.250 ml to 96 well plate (Costar/CorningVWR, NJ) at 2×10 6 c/ml, in RPMI 1640 medium (Gibco BRL). Compounds wereadded and preincubated with cells for 10 min before they were added LPS(Calbiochem, CA) at 1 ug/ml for 5 hours. Supernatent was collected andassayed for TNFα production by standard sandwich ELISA (R&D Systems,Minneapolis, Minn.). Compound inhibition was determined relative tocells cultured with LPS alone.

Example 510 Assay for Her-2 Sheddase Activity

A human breast cell cancer line BT474 (ATCC, Manassas, Va.), was seededat 2×10⁴ cells/well in 100 ul in a 96 well plate (Costar/Corning VWR,NJ) in RPMI 1640 media (In Vitrogen, Carlsbad, Calif.) containing 10%fetal bovine serum (Hyclone, Lenexa, Kans.), and incubated overnight at37° C., 5% CO2. The following morning media was removed and fresh mediawas added back at 100 ul/well. Compounds were added at appropriateconcentrations and the cells were incubated for 72 hour at 37° C., 5%CO2. Supernatants were removed and either tested immediately or storedat −20° C. until testing can be performed. Supernatants were tested at a1/20 dilution for inhibition of Her-2 sheddase by commercial ELISA(Oncogene Research, San Diego, Calif.)). Compound inhibition wasdetermined relative to cells cultured alone.

Example 512 MMP2 Assay

5 mM compound stock was prepared in DMSO. Compound plate was prepared by2-fold dilution for 11-point curve, with highest concentration of 500uM. 1 uL of compound in DMSO was transferred from compound plate to theassay plate. Enzyme solution was prepared in assay buffer with aconcentration of 10 ng/50 ul. Substrate solution was prepared in assaybuffer with a concentration of 20 uM. 50 uL of enzyme solution was addedto the assay plate. The assay plate was incubated for 5 minutes. 50 uLof substrate solution was then added to the assay plate. Protect theplate from the light and incubate the reaction at room temperature for 1hour. The reaction was stopped by adding 10 uL of 500 mM EDTA solution.Read the plate on a plate reader with excitation of 320 nm and emissionof 405 nm.

Example 513 MMP3 Assay

5 mM compound stock was prepared in DMSO. Compound plate was prepared by2-fold dilution for 11-point curve, with highest concentration of 500uM. 1 uL of compound in DMSO was transferred from compound plate to theassay plate. Enzyme solution was prepared in assay buffer with aconcentration of 50 ng/50 ul. Substrate solution was prepared in assaybuffer with a concentration of 20 uM. 50 uL of enzyme solution was addedto the assay plate. The assay plate was incubated for 5 minutes. Add 10ul of 500 mM EDTA to Background wells. 50 uL of substrate solution wasthen added to the assay plate. Protect the plate from the light andincubate the reaction at room temperature for 1 hour. The reaction wasstopped by adding 10 uL of 500 mM EDTA solution. Read the plate on aplate reader with excitation of 320 nm and emission of 405 nm.

Example 514 MMP12 Assay

5 mM compound stock was prepared in DMSO. Compound plate was prepared by2-fold dilution for 11-point curve, with highest concentration of 500uM. 1 uL of compound in DMSO was transferred from compound plate to theassay plate. Enzyme solution was prepared in assay buffer with aconcentration of 10 ng/50 ul. Substrate ((7-methoxycoumarin-4-yl)acetyl-Pro-Leu-Gly-Leu-(3-[2,4-dinitrophenyl]-L-2,3-diaminopropionyl)-Ala-Arg-NH₂)solution was prepared in assay buffer with a concentration of 20 uM. 50uL of enzyme solution was added to the assay plate. The assay plate wasincubated for 5 minutes. Add 10 ul of 500 mM EDTA in the Backgroundwell. 50 uL of substrate solution was then added to the assay plate.Protect the plate from the light and incubate the reaction at Rt. for 1hours. The reaction was stopped by adding 10 uL of 500 mM EDTA solution.Read the plate on a plate reader with excitation of 320 nm and emissionof 405 nm.

Example 515 ADAM10 Assay

5 mM compound stock was prepared in DMSO. Compound plate was prepared by2-fold dilution for 11-point curve, with highest concentration of 500uM. 1 uL of compound in DMSO was transferred from compound plate to theassay plate. Enzyme solution was prepared in assay buffer with aconcentration of 100 ng/50 ul. Substrate((7-methoxycourmarin-4-yl)-acetyl-Pro-Leu-Ala-Gln-Ala-Val-(3-[2,4-dinitrophenyl]-L-2,3-diaminopropionyl)-Arg-Ser-Ser-Ser-Arg-NH₂)solution was prepared in assay buffer with a concentration of 20 uM. 50uL of enzyme solution was added to the assay plate. The assay plate wasincubated for 5 minutes. 50 uL of substrate solution was then added tothe assay plate. Protect the plate from the light and incubate thereaction at 37° C. for 4 hours. The reaction was stopped by adding 10 uLof 500 mM EDTA solution. Read the plate on a plate reader withexcitation of 320 nm and emission

When the above assay protocols are used, the compounds of the presentinvention have IC₅₀ in the range of about 10 nM to about 10 μM for Her2sheddase inhibition, TNF-α inhibition as well as MMP2, MMP12 and MMP3inhibition.

Pharmaceutical Compositions and Uses of the Invention

The compounds of the invention are administered to a mammal, such as ahuman, but can also be administered therapeutically to other mammalssuch as an animal in need of veterinary treatment, e.g., domesticanimals (e.g., dogs, cats, and the like), livestock animals (e.g., cows,sheep, pigs, horses, and the like) and laboratory animals (e.g., rats,mice, guinea pigs, and the like). The mammal treated in the methods ofthe invention is a subject, male or female, in whom modulation of matrixmetalloprotease activity is desired. The term modulation is intended toencompass antagonism, agonism, partial antagonism and/or partialagonism.

In the present specification, the term therapeutically effective amountmeans the amount of the subject compound that will elicit the biologicalor medical response of a tissue, system, non-human animal or human thatis being sought by the researcher, veterinarian, medical doctor or otherclinician.

The compounds of the invention are administered in therapeutic effectiveamounts to treat a disease for example such as rheumatoid arthritis. Atherapeutically effective amount of a compound is that amount whichresults in the inhibition of one or more of the processes mediated bymatrix metalloproteases in a subject with a disease associated withaberrant MMPs activity. Alternatively, a therapeutically effectiveamount of a compound is the quantity required to achieve a desiredtherapeutic and/or prophylactic effect, such as an amount which resultsin the prevention of, or a decrease in, the symptoms associated with adisease associated with aberrant MMP activity.

Diseases or conditions of human or other species which can be treatedwith the inhibitors or modulators of MMP function according to theinvention, include, but are not limited to: inflammatory or allergicdiseases and conditions, including respiratory allergic diseases such asasthma, allergic rhinitis, hypersensitivity lung diseases,hypersensitivity pneumonitis, eosinophilic cellulitis (e.g., Well'ssyndrome), eosinophilic pneumonias (e.g., Loeffler's syndrome, chroniceosinophilic pneumonia), eosinophilic fasciitis (e.g., Shulman'ssyndrome), delayed-type hypersensitivity, interstitial lung diseases(ILD) (e.g., idiopathic pulmonary fibrosis, or ILD associated withrheumatoid arthritis, systemic lupus erythematosus, ankylosingspondylitis, systemic sclerosis, Sjogren's syndrome, polymyositis ordermatomyositis); systemic anaphylaxis or hypersensitivity responses,drug allergies (e.g., to penicillin, cephalosporins),eosinophilia-myalgia syndrome due to the ingestion of contaminatedtryptophan, insect sting allergies; autoimmune diseases, such asrheumatoid arthritis, psoriatic arthritis, multiple sclerosis, systemiclupus erythematosus, myasthenia gravis, juvenile onset diabetes;glomerulonephritis, autoimmune thyroiditis, Behcet's disease; graftrejection (e.g., in transplantation), including allograft rejection orgraft-versus-host disease; inflammatory bowel diseases, such as Crohn'sdisease and ulcerative colitis; spondyloarthropathies; scleroderma;psoriasis (including T-cell mediated psoriasis) and inflammatorydermatoses such as an dermatitis, eczema, atopic dermatitis, allergiccontact dermatitis, urticaria; vasculitis (e.g., necrotizing, cutaneous,and hypersensitivity vasculitis); eosinophilic myositis, eosinophilicfasciitis; neoplastic diseases, cancers with leukocyte infiltration ofthe skin or organs. Other diseases or conditions in which undesirableinflammatory responses are to be inhibited can be treated, including,but not limited to, reperfusion injury, atherosclerosis, certainhematologic malignancies, cytokine-induced toxicity (e.g., septic shock,endotoxic shock), polymyositis, dermatomyositis.

The compounds represented by Formulae I, II, and III of the inventioncan be administered in such oral dosage forms as tablets, capsules (eachof which includes sustained-release or timed-release formulations),pills, powders, granules, elixirs, tinctures, suspensions, syrups, andemulsions. They may also be administered in intravenous (bolus orinfusion), intraperitoneal, subcutaneous, or intramuscular form, allusing dosage forms well known to those of ordinary skill in thepharmaceutical arts. They can be administered alone, but will generallybe administered with a pharmaceutical carrier selected on the basis ofthe chosen route of administration and standard pharmaceutical practice.

The dosage regimen for the compounds of the present invention will, ofcourse, vary depending upon known factors, such as the pharmacodynamiccharacteristics of the particular agent and its mode and route ofadministration; the metabolic stability, rate of excretion, drugcombination, and length of action of that compound the species, age,sex, health, medical condition, and weight of the recipient; the natureand extent of the symptoms; the kind of concurrent treatment; thefrequency of treatment; the specific route of administration, the renaland hepatic function of the patient, and the desired effect. A physicianor veterinarian can determine and prescribe the effective amount of thedrug required to prevent, counter, or arrest the progress of thespecific disorder for which treatment is necessary.

Generally, the daily oral dosage of each active ingredient, when usedfor the indicated effects, will range between about 0.0001 to 1000 mg/kgof body weight, preferably between about 0.001 to 100 mg/kg of bodyweight per day, and most preferably between about 0.1 to 20 mg/kg/day.For intravenous use, the most preferred doses will range from about 0.1to about 10 mg/kg/minute during a constant rate infusion. For oraladministration, the compositions are preferably provided in the form oftablets containing 1.0 to 1000 milligrams of the active ingredient,particularly 1.0, 5.0, 10.0, 15.0. 20.0, 25.0, 50.0, 75.0, 100.0, 150.0,200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and1000.0 milligrams of the active ingredient for the symptomaticadjustment of the dosage to the patient to be treated. The compounds maybe administered on a regimen of 1 to 4 times per day, preferably once ortwice per day.

The compounds of the instant invention can also be administered inintranasal form via topical use of suitable intranasal vehicles, or viatransdermal routes, using transdermal skin patches. When administered inthe form of a transdermal delivery system, the dosage administrationwill of course be continuous rather than intermittent throughout thedosage regimen.

The compounds of the invention are typically administered in admixturewith suitable pharmaceutical diluents, excipients, or carriers(collectively referred to herein as pharmaceutical carriers) suitablyselected with respect to the intended form of administration, that is,oral tablets, capsules, elixirs, syrups and the like, and consistentwith conventional pharmaceutical practices.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic, pharmaceutically acceptable, inert carrier such as lactose,starch, sucrose, glucose, methyl cellulose, magnesium stearate,dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like.For oral administration in liquid form, the oral drug components can becombined with any oral, non-toxic, pharmaceutically acceptable inertcarrier such as ethanol, glycerol, water, and the like. Additionally,when desired or necessary, suitable binders, lubricants, disintegratingagents, and coloring agents can also be incorporated into the mixture.Suitable binders include starch, gelatin, natural sugars such as glucoseor β-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth, or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes, and the like. Lubricants used in thesedosage forms include sodium oleate, sodium stearate, magnesium stearate,sodium benzoate, sodium acetate, sodium chloride, and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum, and the like.

The compounds of the present invention can also be provided to a patientin the form of liposome delivery systems, such as small unilamellarvesicles, large unilamellar vesicles, and multilamellar vesicles.Liposomes can be formed from a variety of phospholipids, such ascholesterol, stearylamine, or phosphatidylcholines.

The compounds of the present invention may also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or poly-ethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, and crosslinked oramphipathic block copolymers of hydrogels.

Dosage forms for the compounds of the invention suitable foradministration may contain from about 0.1 milligram to about 100milligrams of active ingredient per dosage unit. In these pharmaceuticalcompositions the active ingredient will ordinarily be present in anamount of about 0.5-95% by weight based on the total weight of thecomposition.

Gelatin capsules can also be used as dosage forms and may contain theactive ingredient and powdered carriers, such as lactose, starch,cellulose derivatives, magnesium stearate, stearic acid, and the like.Similar diluents can be used to make compressed tablets. Both tabletsand capsules can be manufactured as sustained release products toprovide for continuous release of medication over a period of hours.Compressed tablets can be sugar coated or film coated to mask anyunpleasant taste and protect the tablet from the atmosphere, or entericcoated for selective disintegration in the gastrointestinal tract.

When using liquid dosage forms for oral administration the formulationcan contain coloring and flavoring agents to increase patientacceptance.

Generally, water, a suitable oil, saline, aqueous dextrose (glucose),and related sugar solutions and glycols such as propylene glycol orpolyethylene glycols are suitable carriers for parenteral solutions.Solutions for parenteral administration preferably contain a watersoluble salt of the active ingredient, suitable stabilizing agents, andif necessary, buffer substances. Antioxidizing agents such as sodiumbisulfite, sodium sulfite, or ascorbic acid, either alone or combined,are suitable stabilizing agents. Also used are citric acid and its saltsand sodium EDTA. In addition, parenteral solutions can containpreservatives, such as benzalkonium chloride, methyl- or propyl-paraben,and chlorobutanol. Suitable pharmaceutical carriers are described inRemington's Pharmaceutical Sciences, Mack Publishing Company, a standardreference text in the field of pharmacology.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

The compounds of the present invention may also be administered in theform of suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

For topical use, creams, ointments, jellies, solutions or suspensions,etc., containing the compounds of the present invention are employed. Asused herein, topical application is also meant to include the use ofmouth washes and gargles.

The pharmaceutical compositions and methods of the present invention, inaddition to a compound of Formulae I, II, or III, may further compriseother therapeutically active compounds which are customarilyadministered in the treatment of the aforedescribed pathologicalconditions, provided that such combination(s) does not cause adversereaction in the subject being treated or diminish the activity of thepresently described metalloprotease inhibitors.

Representative useful pharmaceutical dosage-forms for administration ofthe compounds of this invention can be illustrated as follows:

Capsules

A large number of unit capsules can be prepared by filling standardtwo-piece hard gelatin capsules each with 50 milligrams of powderedactive ingredient, 100 milligrams of lactose, 25 milligrams ofcellulose, and 3 milligrams magnesium stearate.

Soft Gelatin Capsules

A mixture of active ingredient in a digestible oil such as soybean oil,cottonseed oil or olive oil may be prepared and injected by means of apositive displacement pump into gelatin to form soft gelatin capsulescontaining 75 milligrams of the active ingredient. The capsules shouldbe washed and dried.

Tablets

Tablets may be prepared by conventional procedures so that the dosageunit is 75 milligrams of active ingredient, 0.15 milligrams of colloidalsilicon dioxide, 4 milligrams of magnesium stearate, 250 milligrams ofmicrocrystalline cellulose, 9 milligrams of starch and 75 milligrams oflactose. Appropriate coatings well known to one skilled in the art maybe applied to increase palatability or delay absorption.

Injectable

A parenteral composition suitable for administration by injection may beprepared by stirring 1.0% by weight of active ingredient in 8% by volumepropylene glycol and water. The solution should be made isotonic withsodium chloride and sterilized.

Suspension

An aqueous suspension can be prepared for oral administration so thateach 5 mL contain 75 mg of finely divided active ingredient, 150 mg ofsodium carboxymethyl cellulose, 3.75 mg of sodium benzoate, 0.75 g ofsorbitol solution, U.S.P., and 0.015 mL of vanillin.

All patents, patent applications and publications cited in thisapplication are hereby incorporated by reference in their entirety forall purposes to the same extent as if each individual patent, patentapplication or publication were so individually denoted.

While the many embodiments of the invention have been disclosed aboveand include presently preferred embodiments, many other embodiments andvariations are possible within the scope of the present disclosure andin the appended claims that follow. Accordingly, the details of thepreferred embodiments and examples provided are not to be construed aslimiting. It is to be understood that the terms used herein are merelydescriptive rather than limiting and that various changes, numerousequivalents may be made without departing from the spirit or scope ofthe claimed invention.

What is claimed is:
 1. A method of treating rheumatoid arthritis in amammalian subject by administering to said mammal in need of suchtreatment an effective amount of a compound according to the followingformula:

or pharmaceutically acceptable salt thereof, wherein: P is-D-E-G-Q-L-T-X-Y; D is C(O); E is absent or is selected from the groupconsisting of C₁₋₁₀alkylene, C₂₋₁₀ alkenylene, and C₂₋₁₀ alkynylene; Gis absent or is selected from the group consisting of O, NR^(a1),S(O)_(p), and C(O); Q is absent or is selected from the group consistingof a C₃₋₁₃ carbocycle substituted with 0-5 R^(b), and a heterocyclewherein said heterocycle is piperazine substituted with 0-5 R^(b); L isabsent or is selected from the group consisting of O, NR^(a1), C(O),C(O)O, OC(O), C(O)NR^(a1), NR^(a1)C(O), OC(O)NR^(a1), NR^(a1)C(O)O,S(O)_(p), S(O)_(p)NR^(a1), and NR^(a1) S(O)_(p); T is absent or isselected from the group consisting of C₁₋₁₀ alkylene, C₂₋₁₀ alkenylene,and C₂₋₁₀ alkynylene; X is absent or is selected from the groupconsisting of O, NR^(a1), S(O)_(p), and C(O); Y is selected from thegroup consisting of H and a C₃₋₁₀ carbocycle substituted with 0-5 R^(c),provided that E, G, Q, L, T, X and Y do not combine to form a N—N, N—O,O—N, O—O, S(O)_(p)—O, O—S(O)_(p) or S(O)_(p)—S(O)_(p) group; M is anaromatic heterocycle selected from the group consisting of pyridyl,quinolyl, and isoquinolyl and substituted with 0-5 R^(d); R^(b) at eachoccurrence is independently selected from the group consisting of C₁₋₆alkyl optionally substituted with R^(c1), O (primary, secondary, ortertiary)C₁-C₈ alkyl, OH, Cl, F, —CN, NO₂, NR^(a)R^(a1), C(O)R^(a),C(O)OR^(a), C(O)NR^(a)R^(a1), R^(a)NC(O)NR^(a)R^(a1), OC(O)NR^(a)R^(a1),R^(a)NC(O)OR^(a1), S(O)₂NR^(a)R^(a1), NR^(a)S(O)₂R^(a2),NR^(a)S(O)₂NR^(a)R^(a1), OS(O)₂NR^(a)R^(a1), S(O)_(p)R^(a2), CF₃, CH₂F,CHF₂, CF₂CH₃, C(CH₃)₂F, OCF₃, OCHF₂, OCH₂CF₃, a C₃₋₁₀ carbocyclicresidue and C₃-C₁₀ carbocyclyl(C₁₋₈)alkyl, wherein said C₃₋₁₀carbocyclic residue, and C₃-C₁₀ carbocyclyl(C₁₋₈)alkyl are optionallysubstituted with R^(c1); R^(a), R^(a1), and R^(a2) at each occurrenceare independently selected from the group consisting of H, C₁-C₈ alkyl,C₂-C₈ alkenyl, C₂-C₈ alkynyl, wherein said alkyl, alkenyl and alkynylgroups are optionally substituted with O (primary, secondary, ortertiary)C₁-C₈, OH, Cl, F, —CN, alkylamino, dialkylamino, alkarylamino,arylamino, alkylcarbonyl, aralkylcarbonyl, arylcarbonyl, carboxyl,alkylcarboxylate, alkylamido, dialkylamido, alkylureidoalkyl,alkylureidodialkyl, carbamoylalkyl, carbamoyldialkyl, alkylcarbamoyl,sulfonamidoalkyl, sulfonamidodialkyl, N-alkylsulfonamidoalkyl,N-alkylsulfonamidoalkyl, N-alkylsufonamidodialkyl, alkylamidosulfonate,dialkylamidosulfonate, alkylsulfinyl, alkylsulfonyl, CF₃, CF₂CF₃, CH₂F,CHF₂, CF₂CH₃, C(CH₃)₂F, OCF₃, and OCH₂CF₃; C₃-C₁₀ carbocycle, C₃-C₁₀carbocyclylalkyl, and wherein said C₃-C₁₀ carbocycle and C₃-C₁₀carbocyclylalkyl may be optionally substituted with one or moresubstituents selected from the group consisting of C₁-C₈ alkyl, O(primary, secondary, or tertiary)C₁-C₈ alkyl, OH, Cl, F, Br, ═O, —CN,NO₂, alkylamino, dialkylamino, alkarylamino, arylamino, alkylcarbonyl,aralkylcarbonyl, arylcarbonyl, carboxyl, alkylcarboxylate, alkylamido,dialkylamido, alkylureidoalkyl, alkylureidodialkyl, carbamoylalkyl,carbamoyldialkyl, alkylcarbamoyl, sulfonamidoalkyl, sulfonamidodialkyl,N-alkylsulfonamidoalkyl, N-alkylsulfonamidoalkyl,N-alkylsufonamidodialkyl, alkylamidosulfonate, dialkylamidosulfonate,alkylsulfinyl, alkylsulfonyl, CF₃, CH₂F, CHF₂, CF₂CH₃, C(CH₃)₂F, OCF₃,and OCH₂CF₃; R^(c) at each occurrence is independently selected from thegroup consisting of C₁₋₆ alkyl optionally substituted with R^(c1),OR^(a), Cl, F, —CN, NO₂, NR^(a)R^(a1), C(O)R^(a), C(O)OR^(a),C(O)NR^(a)R^(a1), R^(a)NC(O)NR^(a)R^(a), OC(O)NR^(a)R^(a1),R^(a)NC(O)OR^(a1), S(O)₂NR^(a)R^(a1), NR^(a)S(O)₂R^(a2),NR^(a)S(O)₂NR^(a)R^(a1), S(O)_(p) R^(a2), CF₃, CH₂F, CHF₂, CF₂CH₃,C(CH₃)₂F, OCF₃, OCHF₂, OCH₂CF₃, a C₃₋₁₀ carbocyclic residue and C₃-C₁₀carbocyclyl(C₁₋₈)alkyl, wherein said C₃₋₁₀ carbocyclic residue andC₃-C₁₀ carbocyclyl(C₁₋₈)alkyl are optionally substituted with R^(c1);R^(c1) at each occurrence is independently selected from the groupconsisting of C₁₋₆ alkyl, OR^(a), Cl, F, Br, ═O, —CN, NO₂, NR^(a)R^(a1),C(O)R^(a), C(O)OR^(a), C(O)NR^(a)R^(a1), OC(O)NR^(a)R^(a1),R^(a)NC(O)OR^(a), S(O)₂NR^(a)R^(a1), NR^(a)S(O)₂R^(a2), S(O)_(p)R^(a2),CF₃, and CH₂F, and CHF₂; R^(d) at each occurrence is independentlyselected from the group consisting of H, C₁₋₆ alkyl optionallysubstituted with R^(c1), OR^(a), Cl, F, Br, ═O, —CN, NO₂, NR^(a)R^(a1),C(O)R^(a), C(O)OR^(a), C(O)NR^(a)R^(a1), R^(a)NC(O)NR^(a)R^(a),OC(O)NR^(a)R^(a1), R^(a)NC(O)OR^(a1), S(O)₂NR^(a)R^(a1),NR^(a)S(O)₂R^(a2), OS(O)₂NR^(a)R^(a1), S(O)_(p)R^(a2), CF₃, CF₂CF₃,CH₂F, CHF₂, CF₂CH₃, C(CH₃)₂F, OCF₃, OCHF₂, OCH₂CF₃, a C₃₋₁₀ carbocyclicresidue and C₃-C₁₀ carbocyclyl(C₁₋₈)alkyl wherein said C₃₋₁₀ carbocyclicresidue and C₃-C₁₀ carbocyclyl(C₁₋₈)alkyl are optionally substitutedwith R^(c1); and p at each occurrence is 0, 1, and
 2. 2. The methodaccording to claim 1, wherein the compound is according to the formula:

wherein: Q is absent or is selected from the group consisting of a C₃₋₁₃carbocycle substituted with 0-5 R^(b), and a heterocycle wherein saidheterocycle is piperazine substituted with 0-5 R^(b); and Y is C₃₋₁₃carbocycle substituted with 0-5 R^(c).
 3. The method according to claim1, wherein the compound exists in the form of a single enantiomer ordiastereomer.
 4. The method according to claim 1, wherein the compoundis selected from the group consisting of:(1S,2S,5R)-N-hydroxy-5-[(6-methylpyridin-3-yl)oxy]-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxamide;(1S,2S,5R)-N-hydroxy-5-[(6-methylpyridin-2-yl)oxy]-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxamide;(1S,2S,5R)-N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]-5-[(2-methylquinolin-4-yl)oxy]cyclohexanecarboxamide;(1S,2S,5R)-5-[(5-chloropyridin-3-yl)oxy]-N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxamide;(1S,2S,5R)-N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]-5-(pyridin-3-yloxy)cyclohexanecarboxamide;(1S,2S,5R)-N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]-5-(quinolin-6-yloxy)cyclohexanecarboxamide;(1S,2S,5R)-N-hydroxy-5-[(4-methylpyridin-2-yl)oxy]-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxamide;(1S,2S,5R)-N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]-5-(pyridin-4-yloxy)cyclohexanecarboxamide;(1S,2S,5R)-N-hydroxy-5-[(2-methylpyridin-3-yl)oxy]-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxamide;and(1S,2S,5R)-N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]-5-(quinolin-4-yloxy)cyclohexanecarboxamide;or a pharmaceutically acceptable salt thereof.
 5. The method accordingto claim 1, wherein the compound is selected from the group consistingof(1S,2S,5R)-N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]-5-(quinolin-6-yloxy)cyclohexanecarboxamide,(1S,2S,5R)-N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]-5-{[2-(trifluoromethyl)quinolin-4-yl]oxy}cyclohexanecarboxamide,(1S,2S,5R)-N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]-5-(quinolin-2-yloxy)cyclohexanecarboxamide,(1S,2S,5R)-N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]-5-(quinolin-3-yloxy)cyclohexanecarboxamide,(1S,2S,5R)-N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]-5-(quinolin-5-yloxy)cyclohexanecarboxamide,(1S,2S,5R)-N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]-5-(quinolin-7-yloxy)cyclohexanecarboxamide,(1S,2S,5R)-N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]-5-(quinolin-8-yloxy)cyclohexanecarboxamide,(1S,2S,5R)-N-hydroxy-5-(isoquinolin-1-yloxy)-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxamide,(1S,2S,5R)-N-hydroxy-5-(isoquinolin-3-yloxy)-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxamide,(1S,2S,5R)-N-hydroxy-5-(isoquinolin-5-yloxy)-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxamide,and(1S,2S,5R)-N-hydroxy-5-(isoquinolin-7-yloxy)-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxamide,or a pharmaceutically acceptable salt thereof.
 6. The method accordingto claim 1, wherein the compound is(1S,2S,5R)-N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]-5-(quinolin-6-yloxy)cyclohexanecarboxamide,or a pharmaceutically acceptable salt thereof.
 7. The method accordingto claim 1, wherein Q is:

Y is phenyl substituted with 0-5 R^(c).
 8. The method according to claim1, wherein -Q-Y is 4-phenylpiperazinyl.
 9. The method according to claim1, wherein the compound is selected from the group consisting of:(1S,2S,5R)-N-hydroxy-2-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]-5-(pyridin-2-yloxy)cyclohexanecarboxamide,(1S,2S,5R)-N-hydroxy-2-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]-5-(pyridin-4-yloxy)cyclohexanecarboxamide,and(1S,2S,5R)-N-hydroxy-2-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]-5-(quinolin-6-yloxy)cyclohexanecarboxamide,or a pharmaceutically acceptable salt thereof.